Amyloid targeting agents and methods of using the same

ABSTRACT

Provided herein is the design and synthesis of novel molecular rotor fluorophores useful for detection of amyloid or amyloid like proteins. The fluorophores are designed to exhibit enhanced fluorescence emission upon associating with amyloid or amyloid like proteins as compared to unbound compound. Also disclosed herein are methods for treating diseases associated with amyloid or amyloid like proteins.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority to U.S.Provisional Application Ser. No. 61/955,366, filed with the U.S. Patentand Trademark on Mar. 19, 2014, the contents of which are herebyincorporated by reference in their entirety and for all purposes.

BACKGROUND OF THE INVENTION

Amyloid plaque accumulation in the brain is the hallmark of manyneurodegenerative disorders, including Alzheimer's disease (AD),Parkinson disease, Down's syndrome and Creutzfeldt-Jakob disease (CJD).Approaches to clinically diagnose and monitor the progression of thesediseases include targeting of amyloid deposits with small-moleculeimaging agents. Accordingly, fluorescence-based small molecule imagingof amyloids is a low cost, accessible, and non-radioactive technique forto detection of the amyloid deposits. Fluorescent compounds thatmaintain their brightness, spectroscopic properties, and specificity forbinding amyloids in neuronal tissue, and exhibit superiorchemical/hydrolytic stability in physiologically relevant solutions aredisclosed herein. The enhanced stability of such compounds is useful inlabeling amyloid deposits in living systems.

SUMMARY OF THE INVENTION

Disclosed herein is a compound of Formula I:

In some aspects of formula I,

EDG is an electron donating group; each Ar is independently C₁-C₁₄arylene or C₁-C₁₄ heteroarylene, each optionally substituted with one ormore R₁; each R₁ is independently halogen, —OR₂, —NR₃R₄, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₅; R₂, R₃ and R₄ are independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₅; eachR₅ is independently halogen, —OR₆, —NR₇R₈, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; R₆, R₇, R₈ and R₈₄ are independently hydrogenor C₁-C₁₀ alkyl; EWG is an electron withdrawing group; WSG is a watersoluble group; X is C═O or SO₂; Y is NH, or S; each x is independentlyan integer from 0-10; each w is independently an integer from 1-5; eachy is independently an integer from 0-10; and z is an integer from 1-10.

In some compounds of Formula I, the substituent R₈₄ is hydrogen orC₁-C₁₀ alkyl. In some compounds of Formula I, R₈₄ is hydrogen. In somecompounds of Formula I, R₈₄ is methyl.

In some compounds of Formula I, the substituent EDG is any electrondonating group, for example, EDG is OR₉, NR₁₀R₁₁, —SR₁₂, —PR₁₃R₁₄,—NR₁₅C(O)R₁₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene,wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene,or heteroarylene is optionally substituted with one or more R₁₇; whereineach R₁₇ is independently halogen, —OR₁₈, —NR₁₉R₂₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; each of R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₈, R₁₉ and R₂₀ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, heterocycloalkyl, C₁-C₁₀ arylene, orC₁-C₁₀ heteroarylene, each of which except for hydrogen is optionallysubstituted with one or more R₂₁ and wherein R₁₀ and R₁₁ are optionallyjoined together to form a heterocycloalkyl or heteroaryl optionallysubstituted with R₂₁; each of R₂₁ is independently halogen, —OR₂₂,—NR₂₃R₂₄, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₂₅; each ofR₂₂, R₂₃ and R₂₄ is independently hydrogen or C₁-C₁₀ alkyl; and each R₂₅is independently C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, cycloalkyl,heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene.

In some compounds of Formula I, the EDG is selected from a groupconsisting of

In some compounds of Formula I, the EDG is

The substituent EWG in Formula I is any electron withdrawing group. Insome compounds of Formula I, EWG is halogen, —CN, —NO₂, —SO₃H,—CR₂₆R₂₇R₂₈, COR₂₉, or COOR₃₀; wherein

each R₂₆, R₂₇ and R₂₈ is independently hydrogen or halogen; R₂₉ ishalogen, hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene,wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene,or heteroarylene is optionally substituted with one or more R₃₁; R₃₀ ishydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₂; and eachR₃₁ and R₃₂ is independently C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene.

In some compounds of Formula I, the EWG is selected from a groupconsisting of F, Cl, Br, —CH═O, NO₂, —CF₃, —CCl₃, —SO₃ and —CN. In somecompounds of Formula I, the EWG is —CN.

The substituent WSG in Formula I is a water soluble group in some cases.In some compounds of Formula I, WSG is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, orC₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₃; wherein

each R₃₃ is independently halogen, —OR₃₄, —NR₃₅R₃₆, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, arylene, orC₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₇;each R₃₄, R₃₅ and R₃₆ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, orC₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₇; each R₃₇ is independently halogen, —OR₃₈,—NR₃₉R₄₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, —(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl), C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; and each of R₃₈, R₃₉ and R₄₀ is independentlyhydrogen or C₁-C₁₀ alkyl.

The substituent WSG in Formula I is a water soluble group in some cases.In some compounds of Formula I, WSG is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₃; wherein

each R₃₃ is independently halogen, —OR₃₄, —NR₃₅R₃₆, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₇;each R₃₄, R₃₅ and R₃₆ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₇; each R₃₇ is independently halogen, —OR₃₈,—NR₃₉R₄₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene; and each ofR₃₈, R₃₉ and R₄₀ is independently hydrogen or C₁-C₁₀ alkyl.

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is polyethylene glycol,polypropylene glycol, co-polymer of polyethylene glycol andpolypropylene glycol, or alkoxy derivatives thereof.

In some compounds of Formula I, WSG is

wherein n is an integer from 1-50 and R₈₁ is hydrogen, a C₁-C₁₀ alkyl, aC₁-C₁₀ alkenyl, or a C₁-C₁₀ alkynyl wherein each wherein the alkyl,alkenyl, or alkynyl is optionally substituted with one or more C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene. In some compounds of Formula I,R₈₁ is methyl or —CH₂—C≡CH.

In some compounds of Formula I, WSG is

wherein n is an integer from 1-50 and R₈₁ is hydrogen or C₁-C₁₀ alkyl.In some compounds of Formula I, R₈₁ is methyl. In some compounds ofFormula I, the variable n is an integer from 1-10. In some compounds ofFormula I, n is 3 or 6.

In some compounds of Formula I, the WSG is

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is —(C₁-C₁₀ alkyl)-R₃₃—R₃₇. In somecompounds of Formula I, WSG is —(C₁-C₁₀ alkyl)-R₃₃—R₃₇ and R₃₃ is C₁-C₁₀heteroarylene. In some compounds of Formula I, WSG is —(C₁-C₁₀alkyl)-R₃₃—R₃₇, R₃₃ is C₁-C₁₀ heteroarylene and R₃₇ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl). In some compounds of Formula I,WSG is WSG is —CH₃—R₃₃—R₃₇. In some compounds of Formula I, WSG is—CH₃—R₃₃—R₃₇ and R₃₃ is triazole. In some compounds of Formula I, WSG is—CH₃—R₃₃—R₃₇, R₃₃ is triazole, and R₃₇ is

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is —(C₁-C₁₀ heteroalkyl)-R₃₃—R₃₇. Insome compounds of Formula I, WSG is —(C₁-C₁₀ heteroalkyl)-R₃₃—R₃₇ andR₃₃ is C₁-C₁₀ heteroarylene. In some compounds of Formula I, WSG is—(C₁-C₁₀ heteroalkyl)-R₃₃—R₃₇ and R₃₃ is C₁-C₁₀ heteroarylene and R³⁷ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula I, WSG is

and p is 1, 2, 3, 4, 5, or 6.

In some compounds of Formula I, WSG is

and p 3.

In some compounds of Formula I, WSG is

and R₃₃ is triazole.

In some compounds of Formula I, WSG is

R₃₃ is triazole, and R₃₇ is

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is

In some cases, the compounds of Formula I is of formula (Ic):

In some cases, the compounds of Formula I is of formula (Id):

In some cases, the compounds of Formula I is of formula (Ie):

In some cases, the compound of Formula I is selected from a groupconsisting of:

wherein n is an integer, for example an integer with value 1-10.

In some cases, the compound of Formula I is selected from:

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.In some cases, the compound of Formula I is(Z)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(R,E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.In some cases, the compound of Formula I is(R,Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethyl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(5-(6-(piperidin-1-yl)naphthalen-2-yl)thiophen-2-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(5-(6-(piperidin-1-yl)naphthalen-2-yl)thiophen-2-yl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(5-(6-(piperidin-1-yl)naphthalen-2-yl)furan-2-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(5-(6-(piperidin-1-yl)naphthalen-2-yl)furan-2-yl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(1-methyl-5-(6-(piperidin-1-yl)naplithalen-2-yl)-1H-pyrrol-2-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(1-methyl-5-(6-(piperidin-1-yl)naphthalen-2-yl)-1H-pyrrol-2-yl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naplithalen-2-yl)-N-(((3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)but-2-enamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(((3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)but-2-enamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naplithalen-2-yl)-N-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethyl)but-2-enamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethyl)but-2-enamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is (E)-2-cyano N (2 (2 (2methoxyethoxy)ethoxy)ethyl)-3-(4-(piperidin-1-yl)phenyl)but-2-enamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(4-(piperidin-1-yl)phenyl)but-2-enamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)but-2-enamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)but-2-enamide.

In some cases, the compound of Formula I is

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)but-2-enamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)but-2-enamide.

The disclosure provides a compound of Formula II

In some aspects of Formula II, EDG is an electron donating group; Ar₂and each Ar₁ is independently C₁-C₁₄ arylene or C₁-C₁₄ heteroarylene,each optionally substituted with one more R₄₁; each R₄₁ is independentlyhalogen, —CN, —OR₄₂, —NR₄₃R₄₄, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₄₅; R₄₂, R₄₃ and R₄₄ are independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₄₅; eachR₄₅ is independently halogen, —OR₄₆, —NR₄₇R₄₈, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; R₄₆, R₄₇ and R₄₈ are independently hydrogen orC₁-C₁₀ alkyl; EWG is an electron withdrawing group; Y is absent, O, NH,or S; WSG is hydrogen or a water soluble group; x is an integer from0-10; y is an integer from 0-10; and z is an integer from 1-10.

The substituent EDG in Formula II is an electron donating group in somecases. In some compounds of Formula II, EDG is OR₄₉, NR₅₀R₅₁, —SR₅₂,—PR₅₃R₅₄, —NR₅₅C(O)R₅₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, arylene, or C₁-C₁₀ heteroarylene,wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene,or heteroarylene is optionally substituted with one or more R₅₇; whereineach R₅₇ is independently halogen, —OR₅₈, —NR₅₉R₆₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, cycloalkyl, heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene; each of R₄₉, R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₈, R₅₉and R₆₀ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl,cycloalkyl, heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene,each of which except for hydrogen is optionally substituted with one ormore R₆₁ and wherein R₅₀ and R₅₁ are optionally joined together to forma heterocycloalkyl or heteroaryl optionally substituted with R₆₁; eachof R₆₁ is independently halogen, —OR₆₂, —NR₆₃R₆₄, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, arylene, orC₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₆₅; each of R₆₂, R₆₃ and R₆₄ is independently hydrogenor C₁-C₁₀ alkyl; and each R₆₅ is independently C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, cycloalkyl, C₁-C₁₀ heterocycloalkyl, arylene, or C₁-C₁₀heteroarylene.

In some compounds of formula II, EDG is selected from a group consistingof

In some compounds of Formula II, EDG is

The substituent EWG in the Formula II is an electron withdrawing groupin some aspects. In some compounds of Formula II, EWG is halogen, —CN,—NO₂, —SO₃H, —CR₆₆R₆₇R₆₈, COR₆₉, or COOR₇₀; wherein each R₆₆, R₆₇ andR₆₈ is independently hydrogen or halogen; R₆₉ is halogen, hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, cycloalkyl, heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₇₁; R₇₀ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₂; each R₇₁ and R₇₂ is independently C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene.

In some compounds of formula II, EWG is selected from a group consistingof F, Cl, Br, —CH═O, NO₂, —CF₃, —CCl₃, —SO₃ and —CN. In some compoundsof Formula II, EWG is —CN.

In some compounds of Formula II, Y is absent, O, NH, or S. In somecompounds of Formula II, Y is absent. In some compounds of Formula II, Yis O, NH, or S.

The substituent WSG in Formula II is a water soluble group in somecases. In some compounds of Formula II, WSG is hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₇₃; wherein each R₇₃ is independentlyhalogen, —OR₇₄, —NR₇₅R₇₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₇; each R₇₄, R₇₅ and R₇₆ is independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₇₇; each R₃₇ is independently halogen,—OR₇₈, —NR₇₉R₈₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,C₁-C₁₀ heterocycloalkyl, —(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl), C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene; and each of R₇₈, R₇₉ and R₈₀ isindependently hydrogen or C₁-C₁₀ alkyl.

The substituent WSG in Formula II is a water soluble group in somecases. In some compounds of Formula II, WSG is hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₇₃; wherein each R₇₃ is independentlyhalogen, —OR₇₄, —NR₇₅R₇₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₇; each R₇₄, R₇₅ and R₇₆ is independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C_(DD) cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₇₇; each R₇₇is independently halogen, —OR₇₈, —NR₇₉R₈₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; and each of R₇₈, R₇₉ and R₈₀ is independentlyhydrogen or C₁-C₁₀ alkyl.

In some compounds of formula II, WSG is hydrogen. In some compounds offormula II, WSG is

In some compounds of formula II, WSG is polyethylene glycol,polypropylene glycol, co-polymer of polyethylene glycol andpolypropylene glycol, or alkoxy derivatives thereof. In some compoundsof formula II, WSG is

wherein n is an integer from 0-50 and R₈₁ is hydrogen, C₁-C₁₀ alkyl, aC₁-C₁₀ alkenyl, or a C₁-C₁₀ alkynyl wherein each wherein the alkyl,alkenyl, or alkynyl is optionally substituted with one or more C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene.

In some compounds of Formula II, WSG is

and R₈₁ is hydrogen. In some compounds of formula II, WSG is

and R₈₁ is methyl. In some compounds of Formula II, WSG is

and R₈₁ is ethyl. In some compounds of Formula II, WSG is

and R₈₁ is CH₂—C≡CH. In some compounds of Formula II, WSG is

and the variable n is any integer of value 0-10. In some compounds ofFormula II, WSG is

and n is 0, 3 or 6.

In some compounds of formula II, WSG is

In some compounds of Formula II, WSG is

In some compounds of formula II, WSG is

In some compounds of Formula II, WSG is

In some compounds of Formula II, WSG is —(C₁-C₁₀ alkyl)-R₇₃—R₇₇. In somecompounds of Formula II, WSG is —(C₁-C₁₀ alkyl)-R₇₃—R₇₇ and R₇₃ isC₁-C₁₀ heteroarylene. In some compounds of Formula II, WSG is —(C₁-C₁₀alkyl)-R₇₃—R₇₇, R₇₃ is C₁-C₁₀ heteroarylene and R₇₇ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl). In some compounds of Formula II,WSG is WSG is —CH₃—R₇₃—R₇₇. In some compounds of Formula II, WSG is—CH₃—R₇₃—R₇₇ and R₇₃ is triazole. In some compounds of Formula II, WSGis —CH₃—R₇₃—R₇₇, R₇₃ is triazole, and R₇₇ is

In some compounds of Formula II, WSG is

In some compounds of Formula II, WSG is

In some compounds of Formula II, WSG is —(C₁-C₁₀ heteroalkyl)-R₇₃—R₇₇.In some compounds of Formula II, WSG is —(C₁-C₁₀ heteroalkyl)-R₇₃—R₇₇and R₇₃ is C₁-C₁₀ heteroarylene. In some compounds of Formula II, WSG is—(C₁-C₁₀ heteroalkyl)-R₇₃—R₇₇ and R₇₃ is —C₁₀ heteroarylene and R₇₇ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula II, WSG is

and p is 1, 2, 3, 4, 5, or 6. In some compounds of Formula II, p isgreater than 6.

In some compounds of Formula II, WSG is

and p 3.

In some compounds of Formula II, WSG is

and R₇₃ is triazole.

In some compounds of Formula II, WSG is

R₇₃ is triazole, and R₇₇ is

In some compounds of Formula II, WSG is

In some compounds of Formula II, WSG is

In some compounds of formula II, each of Ar₁ is independently anaphthylene or a phenylene.

In some compounds of Formula II, Ar₂ is a naphthylene, a phenylene, or apyridyl.

In some compounds of Formula II, Ar₂ is a naphthylene or a phenylene.

In some compounds of Formula II, Ar₂ is a pyridyl.

In some cases, the compound of Formula II is selected from a groupconsisting of

wherein n is an integer, such as an integer with value 0-10. In somecases n is greater than 10.

In some cases, the compound of Formula II is selected from a groupconsisting of

In some cases, the compound of Formula II is

In some cases, the compound of Formula II is2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile.

In some cases, the compound of Formula II

In some cases, the compound of Formula II is4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile.

In some cases, the compound of Formula II is

In some cases, the compound of Formula II is4-(6-(piperidin-1-yl)naphthalen-2-yl)pyridine-3,5-dicarbonitrile.

In some cases, the compound of Formula II is

In some cases, the compound of Formula II is2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-4-(6-(piperidin-1-yl)naphthalen-2-yl)pyridine-3,5-dicarbonitrile.

In some cases, the compound of Formula II is

In some cases, the compound of Formula II is4-(6-(piperidin-1-yl)naphthalen-2-yl)-2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)nicotinonitrile.

In some cases, the compound of Formula II is

In some cases, the compound of Formula II is4-(6-(piperidin-1-yl)naphthalen-2-yl)-2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)nicotinonitrile.

In some cases, the compound of Formula II is

In some cases, the compound of Formula II is4-(6-(piperidin-1-yl)naphthalen-2-yl)-2-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethoxy)nicotinonitrile.

In some cases, the compound of Formula II is

In some cases, the compound of Formula II is4-(6-(piperidin-1-yl)naphthalen-2-yl)-2-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethylamino)nicotinonitrile.

In some embodiments, the disclosure provides a pharmaceuticalcomposition comprising a compound of Formula I or Formula II or FormulaI and Formula II. In some cases, the pharmaceutical composition furthercomprises any pharmaceutically acceptable additive, carrier orexcipient. In some cases, the additive, carrier, or excipient isselected from a group consisting of ethanol, DMSO, polyethylene glycol,polypropylene glycol, aqueous acetate buffers, aqueous citrate buffers,aqueous phosphate buffers, aqueous carbonate buffers, cyclodextrins,corn oil, vitamin E, polysorbates, solutol and bile acids.

In some embodiments, the disclosure provides a composition comprising acompound according the disclosure (Formula I or II) and an amyloid oramyloid like protein. In some cases, the amyloid like protein is Aβpeptide, prion peptide, alpha-synuclein, or superoxide dismutase.

In some embodiments, the disclosure provides a method of detecting anamyloid or amyloid like protein. The method comprise contacting acompound according to Formula I or Formula II with a sample potentiallycomprising the amyloid or amyloid like protein, wherein in presence ofan amyloid or amyloid like protein the compound forms a detectablecomplex, and detecting the formation of the detectable complex such thatthe presence or absence of the detectable complex correlates with thepresence or absence of the amyloid or amyloid like protein. In somecases, the detection of the formation of the detectable complex isperformed by measuring a signal generated by the detectable complex. Insome cases, the signal is an electromagnetic signal, for example afluorescence signal. In some cases, the amyloid or amyloid like proteinis Aβ peptide, prion peptide, alpha-synuclein, or superoxide dismutase.In some cases, the amyloid or amyloid like protein is beta amyloid(1-42) (Aβ (1-42)). In some cases, detection is performed within about 1sec, about 5 sec, about 1 min, about 10 min, about 30 min or about 60min of the contacting of the compound of Formula I or Formula II withthe sample. In some cases, detection is performed within about 1-5minutes of the contacting of the compound of Formula I or Formula II.

In some embodiments, the disclosure provides a method of determining thepresence or absence of one or more disease or condition in a subject. Insome cases, the disease or condition is a disease or conditioncharacterized by protein aggregation or protein misfolding. In someaspects the method comprises administering to the subject an effectiveamount of a compound according to Formula I or Formula II, or apharmaceutical composition thereof, wherein in presence of the diseaseor condition the administered compound forms a detectable complex, anddetecting the detectable complex such that presence or absence ofdetectable complex correlates with the presence or absence of thedisease or condition. In some cases the disease or condition is amyloidbased disease or condition characterized by accumulation of amyloid inthe subject. In some cases, the disease or condition is accompanied byprotein that produces amyloid like morphology. In some cases, thedisease or condition is Alzheimer's disease (AD), Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS), Lewy bodydementia (LBD), or Down's syndrome. In some cases, the disease ofcondition is Alzheimer's disease. In some cases, the disease orcondition is a prion disease or condition, for example Creutzfeldt-Jakobdisease (CJD). In some cases, administration is systemic or topical. Insome cases, the compound is administered to the eye of the subject. Insome cases, detection is performed within about 1 sec, about 5 sec,about 1 min, about 10 min, about 30 min or about 60 min of theadministration of the compound of Formula I or Formula II to thesubject. In some cases, the detection is within about 1-5 min of theadministration of the compound of Formula I or Formula II to thesubject. In some cases, detection of the formation of the detectablecomplex is performed by measuring a signal generated by the detectablecomplex. In some cases, the signal is an electromagnetic signal. In somecases, the signal is a fluorescence signal. In some cases, the effectiveamount of the compound corresponds to about 50-500 mg of compound peradult subject, such as 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470mg, 480 mg, 490 mg, or 500 mg.

In some embodiments, the disclosure provides a method of treating orpreventing a one or more disease or condition, in a subject. In somecases, the method comprises administering to a subject in need oftreatment an effective amount of a compound according to Formula I or IIor a pharmaceutical composition thereof. In some cases, the diseases orconditions is characterized by protein aggregate association or proteinmisfolding. In some cases, the disease or condition is an amyloiddisease or condition. In some cases, non-limiting examples of diseasesor conditions treated by the compounds of the disclosure includeAlzheimer's disease (AD), Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), or Down'ssyndrome. In some cases, the disease or condition is Alzheimer'sdisease. In some cases, the disease or condition is a prion disease orcondition, for example Creutzfeldt-Jakob disease. In some cases, theeffective amount the compound correspond to about 50-500 mg.

In some embodiments, the disclosure provides a screening method. Themethod comprises administering to a subject an effective amount of acompound according to Formula I or Formula II or a pharmaceuticalcomposition thereof, wherein in some cases, the administration of thecompound according to Formula I or Formula II results in formation of adetectable complex. In some cases, the screening method furthercomprises measuring a signal generated by the compound of Formula I orFormula II administered to the subject, and/or by the detectable complexformed by compound of Formula I or Formula II. In some cases, the methodcomprises making a clinical decision based on the measured signal. Insome cases, the signal is an electromagnetic signal. In some cases, thesignal is fluorescence signal. In some cases, the administering issystemic or topical administration. In some cases, the administering isdone to the eye of the subject.

In another aspect, the disclosure provides a kit comprising a compoundaccording to Formula I or Formula II. In some cases, the kit furthercomprises instructions for using the compound for the purpose of bindingto an amyloid or amyloid like protein to form a detectable complex, anddetecting the formation of the detectable complex such that presence orabsence of detectable complex correlates with the presence or absence ofthe amyloid or amyloid like protein. In some cases, the kit furthercomprises instructions for using the compound for binding to an amyloidor amyloid like protein to form a detectable complex, and detectingchanges in abundance of the detectable complex over time such that thechanges in the abundance of the detectable complex over time arecorrelated to changes in abundance of amyloid or amyloid like proteinover time. In some cases, the kit further comprises instructions forcorrelating the changes in the abundance of the detectable complex tomonitor progression of a disease. In some cases, the compound of FormulaI or Formula II is contained in one or more containers as a sterileliquid formulation. In some cases, the compounds of Formula I or FormulaII is contained in one or more container as a sterile freeze-driedformulation. In some cases, the container is a vial. In some cases, thevial is an amber vial. In some cases, the container is also be capableof protecting light sensitive compounds or formulation.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 A Shows a synthetic strategy towards the synthesis of compound 1.

FIG. 1B Shows the structure of compound 1.

FIG. 2A Shows the fluorescence excitation and emission profiles ofcompound 1, measured using 4 μM compound 1 and 5 μM Aβ (1-42) in 5% DMSOin water

FIG. 2B Shows a plot of fluorescence intensity versus concentration ofcompound 1 in the presence of aggregated Aβ(1-42) peptide.

FIG. 3 Shows a synthetic strategy towards the synthesis of compound 2.

FIG. 4 Shows the fluorescence excitation and emission profiles ofcompound 2, measured using 4 μM compound 2 and 5 μM Aβ (1-42) in 5% DMSOin water.

FIG. 5 Shows a synthetic strategy towards the synthesis of compound 3.

FIG. 6A Shows the fluorescence excitation and emission profiles ofcompound 3, measured using 4 μM compound 3 and 5 μM Aβ (1-42) in 5% DMSOin water.

FIG. 6B Shows staining of amyloid deposits in murine AD neuronal tissueby compound 3.

FIG. 7 Shows a synthetic strategy towards the synthesis of compound 5.

FIG. 8A Shows the fluorescence excitation and emission profiles ofcompound 5, measured using 4 μM compound 5 and 5 μM Aβ (1-42) in 5% DMSOin water.

FIG. 8B Shows staining of amyloid deposits in murine AD neuronal tissueby compound 5.

FIG. 9 Shows a synthetic strategy towards the synthesis of compound 17.

FIG. 10 Shows the fluorescence excitation and emission profiles ofcompound 17, measured using 4 μM compound 17 and 5 μM Aβ (1-42) in 5%DMSO in water.

FIG. 11 Shows a synthetic strategy towards the synthesis of compound 18.

FIG. 12 Shows the fluorescence excitation and emission profiles ofcompound 18, measured using 4 μM compound 1 and 5 μM or 10 μM Aβ (1-42)in 5% DMSO in water.

FIG. 13A Shows representative fluorescence micrographs showing thefluorescence labeling of amyloid deposits in hippocampal brain sectionsfrom a mouse model for Alzheimer's disease using compound 1.

FIG. 13. B Shows representative fluorescence micrographs showing thefluorescence labeling of amyloid deposits in hippocampal brain sectionsfrom a mouse model for Alzheimer's disease using compound 2.

FIG. 14 Shows a synthetic strategy towards the synthesis of compound 19.

FIG. 15A Shows the emission profiles of compound 19, measured using 4 μMcompound 19 and 5 μM Aβ (1-42) in 5% DMSO in water.

FIG. 15B Shows staining of amyloid deposits in murine AD neuronal tissueby compound 19.

FIG. 16 Shows a synthetic strategy towards the synthesis of compound 20.

FIG. 17A Shows the emission profiles of compound 20, measured using 4 μMcompound 20 and 5 μM Aβ (1-42) in 5% DMSO in water.

FIG. 17B Shows staining of amyloid deposits in murine AD neuronal tissueby compound 20.

FIG. 18 Shows extrapolated permittivity values (ε_(o)) of Amyloid-β,α-synuclein, or prion proteins using the solvatochromic properties ofcompound 1.

FIG. 19A Shows hydrolysis data of Compound 1 in PBS.

FIG. 19B Shows a solubility vs. pH graph of Compound 1 in water.

FIG. 19C Shows a solubility vs. pH graph of Compound 1 in 50 mM citricacid.

FIG. 20A Shows a 3D rendering assembled from consecutive Z-stack slicesof fluorescence confocal micrographs of flat-mounted, whole retinaltissue from a J20 tg mice injected in vivo with compound 1.Cross-sectional image of the retina from a J20 mouse showing the brightobjects stained with compound 1.

FIG. 20B Shows a 3D rendering assembled from consecutive Z-stack slicesof fluorescence confocal micrographs of flat-mounted, whole retinaltissue from a J20 tg mice injected in vivo with compound 1, only showingthe bright objects stained with an anti-Aβ arrows.

FIG. 21A Shows a bright field retinal image of the retina of ananesthetized wt mouse (pre-injection with compound 1).

FIG. 21B Shows a bright field retinal image of the retina of ananesthetized prion-inoculated mouse (pre-injection with compound 1)

FIG. 21C Shows a bright field retinal image of the retina of wt mousepost-injection with compound 1;

FIG. 21 D Shows a bright field retinal image of the retina ofPrion-inoculated mouse post-injection with compound 1.

FIG. 22A and FIG. 22B Shows a comparison of in vivo and ex vivo imagingof the retina of a prion-infected mouse injected IP with Compound 1.FIG. 22A Shows a Fluorescent image of a live prion-infected mouse dosedwith Compound 1. FIG. 22B Shows Ex vivo image of the same retina(dissected and flat mounted) from the same eye shown in FIG. 22A.

FIG. 23 Shows the true color fluorescence micrograph of a prion plaquedeposited in the neuronal layers of the retina of a prion-inoculatedmouse (156 days) and stained in vivo with Compound 1. Scale bar=50 μm.

FIG. 24A Shows the Mass Analysis of Compound 1 vs Compound 1-HCl salt.

FIG. 24B Shows the ¹H-NMR analysis of Compound 1 vs Compound 1-HCl salt.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, representa straight (i.e. unbranched) or branched chain, or combination thereof,which may be fully saturated, mono- or polyunsaturated and can includedi- and multivalent radicals, having the number of carbon atomsdesignated (i.e. C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of atleast one carbon atoms and at least one heteroatom selected from thegroup consisting of O, N, P, Si and S, and wherein the nitrogen andsulfur atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) 0, N, P and S and Si may beplaced at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—O—CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—CH₂—CH₂—O—CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, O—CH₃, —O—CH₂—CH₃, and —CN. Two or more heteroatomsmay also be consecutive.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,and the like. Examples of heterocycloalkyl include, but are not limitedto, tetrahydropyran, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.Examples of heterocycloalkyl include, but are not limited to glucose,mannose, allose, altrose, gulose, idose, galactose, and talose. Examplesof heterocycloalkyl include, but are not limited to:

and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is meant to include, but not be limited to,fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent which can be a single ring or multiplerings (preferably from 1 to 3 rings) which are fused together (i.e. afused ring aryl) or linked covalently. A fused ring aryl refers tomultiple rings fused together wherein at least one of the fused rings isan aryl ring.

The term “heteroaryl” refers to aryl groups (or rings) that contain fromone to four heteroatoms selected from N, O, and S, wherein the nitrogenand sulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. Thus, the term “heteroaryl” includes fused ringheteroaryl groups (i.e. multiple rings fused together wherein at leastone of the fused rings is a heteroaromatic ring). A 5,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 5members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers totwo rings fused together, wherein one ring has 6 members and the otherring has 6 members, and wherein at least one ring is a heteroaryl ring.And a 6, 5-fused ring heteroarylene refers to two rings fused together,wherein one ring has 6 members and the other ring has 5 members, andwherein at least one ring is a heteroaryl ring. A heteroaryl group canbe attached to the remainder of the molecule through a carbon orheteroatom. Non-limiting examples of aryl and heteroaryl groups includephenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, triazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.

An “arylene” and a “heteroarylene,” alone or as part of anothersubstituent means a divalent radical derived from an aryl andheteroaryl, respectively.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

As used herein, the term “heteroatom” or “ring heteroatom” is meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

As used herein, the term “about” a number or range of numbers refers tothat number or range of numbers plus or minus 10% of that number or thatrange of numbers minus 10% of the lowest listed member of the range andplus 10% of the highest listed member of the range.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentdisclosure contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present disclosure contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

In some cases, the compounds of the present disclosure exist as salts,such as with pharmaceutically acceptable acids. The present disclosureconemplates such salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures),succinates, benzoates and salts with amino acids such as glutamic acid.In some cases, these salts are prepared, for example, by methods knownto those skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties insome cases, such as solubility in polar solvents.

In addition to salt forms, the present disclosure provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentdisclosure. Additionally, prodrugs can be converted to the compounds ofthe present disclosure by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present disclosure when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present disclosure can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present disclosure. In some cases,certain compounds of the present disclosure exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated by the present disclosure and areintended to be within the scope of the present disclosure.

Certain compounds of the present disclosure possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,tautomers, geometric isomers and individual isomers are encompassedwithin the scope of the present disclosure. In some embodiments,compounds which are known in the art to be too unstable to synthesizeand/or isolate are excluded.

In some cases, the compounds of the present disclosure contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. In some cases, the compounds are radiolabeledwith radioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present disclosure, whether radioactive or not, are encompassedwithin the scope of the present disclosure.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, pathology or condition,including any objective or subjective parameter such as abatement;remission; diminishing of symptoms or making the injury, pathology orcondition more tolerable to the patient; slowing in the rate ofdegeneration or decline; making the final point of degeneration lessdebilitating; improving a patient's physical or mental well-being. Thetreatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,the certain methods presented herein successfully treat cancer bydecreasing the incidence of cancer, in inhibiting its growth and orcausing remission of cancer.

An “effective amount” is an amount of a compound described hereinsufficient to contribute to the treatment, prevention, or reduction of asymptom or symptoms of a disease, or to inhibit effects of an amyloidrelative to the absence of the compound. In some cases, where recited inreference to a disease treatment, an “effective amount” is also referredto as a “therapeutically effective amount.” A “reduction” of a symptomor symptoms (and grammatical equivalents of this phrase) meansdecreasing of the severity or frequency of the symptom(s), orelimination of the symptom(s). A “prophylactically effective amount” ofa drug is an amount of a drug that, when administered to a subject, willhave the intended prophylactic effect, e.g., preventing or delaying theonset (or reoccurrence) a disease, or reducing the likelihood of theonset (or reoccurrence) of a disease or its symptoms. In some cases, thefull prophylactic effect does not necessarily occur by administration ofone dose, and occur only after administration of a series of doses. Insome cases, a prophylactically effective amount is administered in oneor more administrations. An “activity decreasing amount,” as usedherein, refers to an amount of antagonist required to decrease theactivity of an enzyme relative to the absence of the antagonist. A“function disrupting amount,” as used herein, refers to the amount ofantagonist required to disrupt the function of an osteoclast orleukocyte relative to the absence of the antagonist.

In some cases, diseases or conditions that are treated with thecompounds of the present disclosure include diseases or conditionsaccompanied by protein that produces amyloid like morphology and diseaseor conditions associated with the formation of abnormal proteinstructures, protein aggregation, or protein misfolding. In some cases,an abnormal protein structure is a protein structure that arises when aprotein or peptide refolds from the three-dimensional structure, whichit generally adopts in healthy individuals, into a differentthree-dimensional structure, which is associated with a pathologicalcondition. In some cases, diseases or conditions that are treated withthe compounds of the present disclosure are diseases or conditionsassociated with amyloid or amyloid-like proteins. In some cases, suchdiseases are referred to as amyloid based diseases or conditions.Amyloid based diseases or conditions, include any disease or conditionthat is associated with amyloid or amyloid-like protein and ischaracterized, in part, by the buildup of extracellular deposits ofamyloid or amyloid-like material. In the context of this disclosure,amyloid based diseases or conditions also include disease or conditionsaccompanied by protein that produces amyloid like morphology. Thesediseases include, but are not limited to, neurological disorders such asAlzheimer's disease (AD), Parkinson's disease, Huntington's disease,diseases or conditions characterized by a loss of cognitive memorycapacity such as, for example, mild cognitive impairment (MCI), Lewybody dementia, Down's syndrome, hereditary cerebral hemorrhage withamyloidosis (Dutch type); the Guam Parkinson-Dementia complex. Otherdiseases which are based on or associated with amyloid-like proteins areprogressive supranuclear palsy, multiple sclerosis; Creutzfeldt Jacobdisease, Parkinson's disease, HIV-related dementia, ALS (amyotropiclateral sclerosis), inclusion-body myositis (IBM), Adult Onset Diabetes;senile cardiac amyloidosis; endocrine tumors, and other diseases,including amyloid-associated ocular diseases that target differenttissues of the eye, such as the visual cortex, including cortical visualdeficits; the anterior chamber and the optic nerve, including glaucoma;the lens, including cataract due to beta-amyloid deposition; thevitreous, including ocular amyloidosis; the retina, including primaryretinal degenerations and macular degeneration, in particularage-related macular degeneration; the optic nerve, including optic nervedrusen, optic neuropathy and optic neuritis; and the cornea, includinglattice dystrophy.

The term “amyloid protein” is intended to denote a protein which isinvolved in the formation of fibrils, plaques and/or amyloid deposits,either by being part of the fibrils, plaques and/or deposits as such orby being part of the biosynthetic pathway leading to the formation ofthe fibrils, plaques and/or amyloid deposits. In the present context theterm “protein” or is intended to mean both short peptides of from 2 to10 amino acid residues, oligopeptides of from 11 to 100 amino acidresidues, polypeptides of more than 100 amino acid residues, and fulllength proteins. The terms also encompass peptides having substantialsimilarity to amyloid proteins, such as, e.g., structural variants. Insome cases, the proteins occur naturally or be syntheticallyconstructed. The term amyloid protein or amyloid like protein alsoincludes amyloidgenic proteins and proteins that produce amyloid likemorphology.

The term “substantial similarity” means that two peptide sequences, whenoptimally aligned, share at least 50% sequence identity, or at least 60%sequence identity, or at least 70% sequence identity, or at least 80%sequence identity, or at least 90 percent sequence identity, or at least95 percent sequence identity or more (e.g., 99% sequence identity).Preferably, residue positions, which are not identical, differ byconservative amino acid substitutions. Conservative amino acidsubstitutions refer to the interchangeability of residues having similarside chains. For example, a group of amino acids having aliphatic sidechains is glycine, alanine, valine, leucine, and isoleucine; a group ofamino acids having aliphatic-hydroxyl side chains is serine andthreonine; a group of amino acids having amide-containing side chains isasparagine and glutamine; a group of amino acids having aromatic sidechains is phenylalanine, tyrosine, and tryptophan; a group of aminoacids having basic side chains is lysine, arginine, and histidine; and agroup of amino acids having sulfur-containing side chains is cysteineand methionine. Preferred conservative amino acids substitution groupsare: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine,alanine-valine, and asparagine-glutamine. In some cases, residuepositions, which are not identical are also composed of peptide analogs,including unnatural amino acids or derivatives of such. Analogstypically differ from naturally occurring peptides at one, two or a fewpositions, often by virtue of conservative substitutions. Some analogsalso include unnatural amino acids or modifications of N or C terminalamino acids at one, two or a few positions. Examples of unnatural aminoacids are D-amino acids, alpha, alpha-disubstituted amino acids, N-alkylamino acids, lactic acid, 4-hydroxyproline, y-carboxyglutamate,epsilon-N,N,N-trimethyllysi-ne, epsilon-N-acetyllysine, O-phosphoserine,N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine,omega.-N-methylarginine, and isoaspartic acid.

Overview

In some cases, the disclosure provides novel compounds that are employedin the detection, diagnosis, treatment, and monitoring of diseases orconditions associated with protein aggregation or protein misfolding. Insome cases, the compounds of the disclosure are also employed in thedetection, diagnosis, treatment, and monitoring of amyloid baseddiseases or conditions. The disclosure further provides pharmaceuticalcompositions comprising these compounds and the use of these compoundsfor the preparation of medicaments for the treatment of such diseases orconditions.

The compounds of the disclosure are designed form a detectable complexin presence of an amyloid or amyloid-like protein. In some cases, thecompounds disclosed herein are classified as molecular rotorfluorophores. The compounds comprise an electron rich donor moietycovalently connected to a conjugated pi system (for example, to anaromatic pi network) and in electronic conjugation to an electron pooracceptor moiety covalently connected elsewhere on the pi system. Thecompounds also comprise one or more single bonds between the donor andacceptor that can rotate freely under standard thermal control of theenvironment in the temperature range of interest. The rotation of thesingle bond allows the donor and acceptor to remain substantiallydecoupled in the absence of binding to a protein and thus the compoundsexhibit poor fluorescence signal. However, in presence of an amyloid oramyloid-like protein these compounds may bind to amyloid or amyloid-likeproteins. Accordingly, the rotatable single bonds may become essentiallyfrozen and the electronic coupling between the donor and acceptor may besubstantially enhanced. In some cases, it leads to a strong fluorescencesignal upon irradiation with an appropriate wavelength of light. In somecases, the strong fluorescence enhancement of these compounds uponbinding to amyloid or amyloid-like proteins compared to the freecompound in solution results in excellent signal to noise ratio and makeit possible to image amyloid or amyloid-like proteins with highsensitivity.

Also provided herein is a method for detecting an amyloid oramyloid-like protein. The method comprises contacting a compound of thedisclosure or a pharmaceutical composition thereof with the samplepotentially comprising the amyloid or amyloid-like protein, wherein inpresence of an amyloid or amyloid-like protein the compound forms adetectable complex, and detecting the formation of the detectablecomplex such that the presence or absence of the detectable complexcorrelates with the presence or absence of the amyloid or amyloid likeprotein. In some cases, the detection of the detectable complex in themethods of the disclosure comprises illuminating the sample with lightof an appropriate wavelength and detecting light received from thesample. In some cases, the wavelength of the illuminating light isvaried and selected according to the fluorescence excitation andemission spectrum of the detectable complex. In some cases, thedetectable complex has a fluorescent excitation peak in the range of350-500 nm, and the fluorescence emission spectrum of the detectablecomplex in the range of 500-550 nm. In some cases, the illuminatinglight has a wavelength of 350-450 nm (example 400 nm). In some cases,amyloid or amyloid like protein or peptide is detected by the methods ofthe disclosure. In some cases, the method is used to detect the presenceor absence of Aβ peptide, prion peptide, alpha-synuclein, or superoxidedismutase.

The disclosure also provides a method of determining the presence orabsence of one or more disease or condition in a subject. The methodcomprises administering to the subject an effective amount of a compoundof the disclosure or a pharmaceutical composition thereof, wherein inpresence of the a disease or condition the administered compound forms adetectable complex, and detecting the formation of the detectablecomplex such that presence or absence of the detectable complexcorrelates with the presence or absence of the disease or condition. Insome cases, the method includes comparing the amount of the detectablecomplex to a normal control value, wherein an increase in the amount ofthe detectable complex compared to a normal control value indicates thatsaid patient is suffering from or is at risk of developing the diseaseor condition. Also provided herein is a method of treating, preventingor alleviating the symptoms of a disease or condition in a subject. Themethod comprises administering to a subject in need of treatment aneffective amount of a compound of the disclosure or a pharmaceuticalcomposition thereof. In some cases, the subject is a mammal. In somecase, the subject is a primate (such as a human), canine, feline, ovine,bovine and the like.

In some cases, the disease or condition is a disease or conditioncharacterized by protein aggregation or misfolding. In some cases, thedisease or condition is also an amyloid based disease or condition. Insome cases, the amyloid-based disease or condition is any disease orcondition associated with the increased or decreased presence of amyloidor amyloid like proteins, such as the presence of amyloid plaques orother amyloid aggregates. In some cases, the disease is a neuronaldisease. In some cases, the disease is a neurodegenerative diseases, inwhich amyloid-beta peptides, oligomers, fibrils, or plaques areimplicated. In some cases, the disease is Alzheimer's disease,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis(ALS), Lewy body dementia (LBD), or Down's syndrome. In some cases, theamyloid-based disease or condition also includes ocular diseasesassociated with pathological abnormalities/changes in the tissues of thevisual system, particularly associated with amyloid-beta-relatedpathological abnormalities/changes in the tissues of the visual system,such as, for example, neuronal degradation. In some cases, pathologicalabnormalities occur, for example, in different tissues of the eye, suchas the visual cortex leading to cortical visual deficits; the anteriorchamber and the optic nerve leading to glaucoma; the lens leading tocataract due to beta-amyloid deposition; the vitreous leading to ocularamyloidosis; the retina leading to primary retinal degeneration andmacular degeneration; the optic nerve leading to optic nerve drusen,optic neuropathy and optic neuritis; and the cornea leading to latticedystrophy.

In some cases, the compounds and the methods of the disclosure are alsoused to monitor minimal residual disease in a patient followingtreatment with a compound or a mixture according to the disclosure. Insome cases, a sample or a specific body part or body area suspected tocontain the amyloid antigen is contacted with a compound of thedisclosure, and the compound is allowed to bind to the amyloid oramyloid like protein to form a detectable complex. In some cases, theformation of the detectable complex is detected and its presence orabsence is correlated with the presence or absence of amyloid or amyloidlike protein in the sample or specific body part or area. In some cases,the amount of said detectable complex is compared to a normal controlvalue, wherein an increase in the amount of said detectable complexcompared to a normal control value indicates that the patient may stillbe suffering from a minimal residual disease.

In some cases, the compounds and methods disclosed herein are useful forpredicting responsiveness of a patient to a treatment. In some cases, asample or a specific body part or body area suspected to contain theamyloid or amyloid like protein is brought into contact with a compoundof the disclosure, such that in presence of the amyloid or amyloid likeprotein the compound binds to the amyloid or amyloid like protein toform a detectable complex. In some cases, the formation of thedetectable complex is detected and the presence or absence of thedetectable complex is correlated with the presence or absence of amyloidor amyloid like protein in the sample or specific body part or area. Insome cases, the amount of the detectable complex before and after onsetof the treatment is compared, such that a decrease in the amount of thedetectable complex indicates that the patient is being responsive to thetreatment.

Compounds

In one aspect the disclosure provides a compound of Formula I:

An Ar in Formula I is independently C₁-C₁₄ arylene or C₁-C₁₄heteroarylene, each optionally substituted with one or more R₁; whereineach R₁ is independently halogen, —CN, —OR₂, —NR₃R₄, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₅; R₂, R₃ and R₄ are independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₅; eachR₅ is independently halogen, —OR₆, —NR₇R₈, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; R₆, R₇ and R₈ are independently hydrogen orC₁-C₁₀ alkyl.

R₈₄ in Formula I is hydrogen or C₁-C₁₀ alkyl. In some compounds ofFormula I, R₈₄ is hydrogen. In some compounds of Formula I, R₈₄ isC₁-C₁₀ alkyl. In some compounds of Formula I, R₈₄ is methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, neptyl or decyl. In somecompounds of Formula I, R₈₄ is methyl.

The substituent EDG in Formula I is an electron donor group, as known inthe art. In some compounds of Formula I, EDG is any atom or functionalgroup that is capable of donating some of its electron density into aconjugated pi system, thus making the pi system more nucleophilic. Insome compounds of Formula I, the EDG is —OR₉, —NR₁₀R₁₁, —SR₁₂, —PR₁₃R₁₄,—NR₁₅C(O)R₁₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene,wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene,or heteroarylene is optionally substituted with one or more R₁₇; whereineach R₁₇ is independently halogen, —OR₁₈, —NR₁₉R₂₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; each of R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₈, R₁₉ and R₂₀ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, each of which except for hydrogen is optionallysubstituted with one or more R₂₁ and wherein R₁₀ and R₁₁ are optionallyjoined together to form a heterocycloalkyl or heteroaryl optionallysubstituted with R₂₁; each of R₂₁ is independently halogen, —OR₂₂,—NR₂₃R₂₄, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₂₅; each ofR₂₂, R₂₃ and R₂₄ is independently hydrogen or C₁-C₁₀ alkyl; and each R₂₅is independently C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene.

In some compounds of Formula I, the EDG is selected from a groupconsisting of

In some compounds of Formula I, the EDG is

In some compounds of formula II, EDG is

EWG is an electron withdrawing group. In some compounds of Formula I,the electron withdrawing group as used herein is any atom or group thatis capable of drawing electron density from neighboring atoms towardsitself, either by resonance or inductive effects. In some compounds ofFormula I, EWG is selected from a group consisting of halogen, —CN,—NO₂, —SO₃H, —CR₂₆R₂₇R₂₈, —COR₂₉, or —COOR₃₀; wherein each R₂₆, R₂₇ andR₂₈ is independently hydrogen or halogen; R₂₉ is halogen, hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₁; R₃₀ ishydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₂; and eachR₃₁ and R₃₂ is independently C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene.

In some compounds of Formula I, the EWG is selected from a groupconsisting of —F, —Cl, —Br, —CH═O, NO₂, —CF₃, —CCl₃, —SO₃ and —CN. Insome compounds of Formula I, the EWG is F, Cl, or Br. In some compoundsof Formula I, the EWG is —CN.

WSG is a water soluble group. In some compounds of Formula I, the WSGgroup in Formula I serves to alter the solubility of the compounds ofFormula I in an aqueous systems. In some compounds of Formula I, WSG ishydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₃; whereineach R₃₃ is independently halogen, —OR₃₄, —NR₃₅R₃₆, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₇; each R₃₄, R₃₅ and R₃₆ is independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₇; each R₃₇is independently halogen, —OR₃₈, —NR₃₉R₄₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl), C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene; and each of R₃₈, R₃₉ and R₄₀ is independently hydrogen orC₁-C₁₀ alkyl.

WSG is a water soluble group. The WSG group in Formula I serves to alterthe solubility of the compounds of Formula I in an aqueous systems. Insome compounds of Formula I, WSG is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₃; wherein

each R₃₃ is independently halogen, —OR₃₄, —NR₃₅R₃₆, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₇; each R₃₄, R₃₅ and R₃₆ is independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₇; each R₃₇is independently halogen, —OR₃₈, —NR₃₉R₄₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; andeach of R₃₈, R₃₉ and R₄₀ is independently hydrogen or C₁-C₁₀ alkyl.

In some compounds of Formula I, the WSG is

In some compounds of Formula I, WSG is polyethylene glycol,polypropylene glycol, co-polymer of polyethylene glycol andpolypropylene glycol, or alkoxy derivatives thereof. In some compoundsof Formula I, WSG is

wherein n is an integer from 1-50 and R₈₁ is hydrogen, C₁-C₁₀ alkyl, aC₁-C₁₀ alkenyl, or a C₁-C₁₀ alkynyl wherein each wherein the alkyl,alkenyl, or alkynyl is optionally substituted with one or more C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene. In some compounds of Formula I,WSG is

and R₈₁ is hydrogen. In some compounds of Formula I, WSG is

and R₈₁ is methyl. In some compounds of Formula I, WSG is

and R₈₁ is ethyl.

In some compounds of Formula I, WSG is

and R₈₁ is CH₂—C≡CH.

In some compounds of Formula I, WSG is

and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

In some compounds of Formula I, WSG is

and n is an integer of value 1-10, 1-20, 1-30, 1-40, 1-50, 10-20, 10-30,10-40, 10-50, 20-30, 20-40, 20-50, 30-40, 30-50, or 40-50.

In some compounds of Formula I, WSG is

and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some compounds of FormulaI, WSG is

and n is 3 or 6.

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is

In some compounds of Formula I, the WSG is

wherein each R₈₂ is hydrogen or C₁-C₁₀ alkyl.

In some compounds of Formula I, each R₈₂ is independently a hydrogen,methyl, ethyl, propyl, or butyl.

In some compounds of Formula I, the WSG is

In some compounds of Formula I, the WSG is

In some compounds of Formula I, the WSG is

wherein each R₈₃ is hydrogen or C₁-C₁₀ alkyl. In some compounds ofFormula I, each R₈₃ is independently a hydrogen, methyl, ethyl, propyl,or butyl.

In some compounds of Formula I the WSG is

In some compound of Formula I the WSG is

In some compounds of Formula I, WSG is —(C₁-C₁₀ alkyl)-R₃₃—R₃₇. In somecompounds of Formula I, WSG is —(C₁-C₁₀ alkyl)-R₃₃—R₃₇ and R₃₃ is C₁-C₁₀heteroarylene. In some compounds of Formula I, WSG is —(C₁-C₁₀alkyl)-R₃₃—R₃₇, R₃₃ is C₁-C₁₀ heteroarylene and R₃₇ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula I, WSG is —CH₃—R₃₃—R₃₇.

In some compounds of Formula I, WSG is —CH₃—R₃₃—R₃₇ and R₃₃ is triazole,imidazole, or pyrrazole.

In some compounds of Formula I, WSG is —CH₃—R₃₃—R₃₇ and R₃₃ is triazole.

In some compounds of Formula I, WSG is —CH₃—R₃₃—R₃₇ and R₃₃ is1,2,4-triazole.

In some compounds of Formula I, WSG is —CH₃—R₃₃—R₃₇ and R₃₃ is1,2,3-triazole.

In some compounds of Formula I, WSG is —CH₃—R₃₃—R₃₇, R₃₃ is1,2,3-triazole and R₃₇ is —(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula I, WSG is —CH₃—R₃₃—R₃₇, R₃₃ is1,2,3-triazole and R₃₇ is —(C₁alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula I, WSG is —CH₃—R₃₃—R₃₇, R₃₃ is1,2,3-triazole, R₃₇ is —(C₁alkyl)(C₁-C₁₀heretocycloalkyl), andC₁-C₁₀heretocycloalkyl is a tetrahydropyran derivative.

In some compounds of Formula I, WSG is —CH₃—R₃₃—R₃₇, R₃₃ is1,2,3-triazole, and R₃₇ is

In some compounds of Formula I, WSG is

wherein each R₈₇ is hydrogen, C₁-C₁₀ alkyl, or —C(═O)C₁-C₁₀ alkyl. Insome compounds of Formula I, each R₈₇ is independently a hydrogen,methyl, ethyl, propyl, butyl, acetate, propionate, or butyrate. In somecompounds of Formula I, each R₈₇ is independently a hydrogen or methyl.In some compounds of Formula I, each R₈₇ is independently a methyl oracetate.

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is

In some compounds of Formula I, WSG is —(C₁-C₁₀ heteroalkyl)-R₃₃—R₃₇. Insome compounds of Formula I, WSG is —(C₁-C₁₀ heteroalkyl)-R₃₃—R₃₇ andR₃₃ is C₁-C₁₀ heteroarylene. In some compounds of Formula I, WSG is—(C₁-C₁₀ heteroalkyl)-R₃₃—R₃₇ and R₃₃ is C₁-C₁₀ heteroarylene and R³⁷ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula I, WSG is

and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

In some compounds of Formula I, p is an integer of value 1-10, 1-20,1-30, 1-40, 1-50, 10-20, 10-30, 10-40, 10-50, 20-30, 20-40, 20-50,30-40, 30-50, or 40-50.

In some compounds of Formula I, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some compounds of Formula I, p is 3 or 6.

In some compounds of Formula I, WSG is

and p 3.

In some compounds of Formula I, WSG is

and R₃₃ is a C₁-C₁₀ heteroarylene.

In some compounds of Formula I, WSG is

and R₃₃ is a C₅ heteroarylene.

In some compounds of Formula I, WSG is

and R₃₃ is triazole, imidazole, or pyrrazole.

In some compounds of Formula I, WSG is

and R₃₃ is triazole.

In some compounds of Formula I, WSG is

and R₃₃ is 1, 2, 4-triazole. In some compounds of Formula I, WSG is

and R₃₃ is 1, 2, 3-triazole.

In some compounds of Formula I, WSG is

R₃₃ is 1, 2, 3-triazole, and p is 3.

In some compounds of Formula I, WSG is

R₃₃ is 1,2,3-triazole and R₃₇ is —(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula I, WSG is

R₃₃ is 1,2,3-triazole and R₃₇ is —(C₁alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula I, WSG is

R₃₃ is 1,2,3-triazole, R₃₇ is a tetrahydropyran derivative.

In some compounds of Formula I, WSG is

R₃₃ is 1,2,3-triazole, and R₃₇ is

In some compounds of Formula I, WSG is

R₃₃ is 1,2,3-triazole, R₃₇ is

and p is 3.

In some compounds of Formula I, WSG is

wherein each R₈₇ is hydrogen, C₁-C₁₀ alkyl, or —C(═O)C₁-C₁₀ alkyl. Insome compounds of Formula I, each R₈₇ is independently a hydrogen,methyl, ethyl, propyl, butyl, acetate, propionate, or butyrate. In somecompounds of Formula I, each R₈₇ is independently a hydrogen or methyl.In some compounds of Formula I, each R₈₇ is independently a methyl oracetate.

In some compounds of Formula I, WSG

In some compounds of Formula I, WSG is

In some compounds of Formula I, X is C═O or SO₂. In some compounds ofFormula I, X is C═O. In some compounds of Formula I, X is SO₂.

In some compounds of Formula I, Y is NH or S. In some compounds ofFormula I, Y is NH. In some compounds of Formula I, Y is S.

The variable w in Formula I is an integer from 1-5. In some compounds ofFormula I, w is 1. In some compounds of Formula I, w is 2. In somecompounds of Formula I, w is 3. In some compounds of Formula I, w is 4.In some compounds of Formula I, w is 5.

The variable x in Formula I is an integer from 0-10. In some compoundsof Formula T, x is 0. In some compounds of Formula I, x is 1. In somecompounds of Formula I, x is 2. In some compounds of Formula I, x is 3.In some compounds of Formula I, x is 4. In some compounds of Formula I,x is 5. In some compounds of Formula I, x is 6. In some compounds ofFormula I, x is 7. In some compounds of Formula I, x is 8. In somecompounds of Formula I, x is 9. In some compounds of Formula I, x is 10.

The variable y in Formula I is an integer from 0-10. In some compoundsof Formula I, y is 0. In some compounds of Formula I, y is 1. In somecompounds of Formula I, y is 2. In some compounds of Formula I, y is 3.In some compounds of Formula I, y is 4. In some compounds of Formula I,y is 5. In some compounds of Formula I, y is 6. In some compounds ofFormula I, y is 7. In some compounds of Formula I, y is 8. In somecompounds of Formula I, y is 9. In some compounds of Formula I, y is 10.

The variable z in Formula I is an integer from 1-10. In some compoundsof Formula I, z is 1. In some compounds of Formula I, z is 2. In somecompounds of Formula I, z is 3. In some compounds of Formula I, z is 4.In some compounds of Formula I, z is 5. In some compounds of Formula I,z is 6. In some compounds of Formula I, z is 7. In some compounds ofFormula I, z is 8. In some compounds of Formula I, z is 9. In somecompounds of Formula I, z is 10.

In some compounds of Formula I, x is 0, w is 1, y is 0, z is 1, X isC═O, and Y is NH.

In some compounds of Formula I, x is 0, w is 1, y is 0, z is 1, X isSO₂, and Y is NH.

In some compounds of Formula I, x is 0, w is 2, y is 0, z is 1, X isC═O, and Y is NH.

In some compounds of Formula I, x is 0, w is 2, y is 0, z is 1, X isSO₂, and Y is NH.

In one aspect the disclosure provides a compound of Formula Ia:

wherein EDG, Ar, R₈₄, x, w, y, z, EWG, and WSG are defined as above forFormula I.

In one aspect the disclosure provides a compound of Formula Ib:

wherein EDG, Ar, R₈₄, x, w, y, z, EWG, and WSG are defined above forFormula I.

In one aspect the disclosure provides a compound of Formula Ic:

wherein EDG, Ar, R₈₄, X, Y, EWG, and WSG are defined above for FormulaI.

In one aspect the disclosure provides a compound of Formula Id:

wherein EDG, R₈₄, Ar, EWG, and WSG are defined as above for Formula I.

In one aspect the disclosure provides a compound of Formula Ie:

wherein EDG, R₈₄, Ar, EWG, and WSG are defined as above for Formula I.

In some cases the compound of Formula I is selected from a groupconsisting of

wherein n is an integer with value 1-50. In some cases, n is a integerof value 1-10, e.g. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In other cases the compound of Formula I is selected from a groupconsisting of

In other cases the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

wherein p is an integer with value 1-50. In some cases, p is a integerof value 1-10, e.g. p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some cases, the compound of Formula I is selected from a groupconsisting of

wherein n is an integer with value 1-50. In some cases, n is a integerof value 1-10, e.g. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In other cases the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In other cases the compound of Formula I is selected from a groupconsisting of

In some cases the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

wherein n is an integer with value 1-50. In some cases, n is a integerof value 1-10, e.g. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some cases, the compound of Formula I is selected from a groupconsisting of

wherein n is an integer with value 1-50. In some cases, n is a integerof value 1-10, e.g. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some cases, the compound of Formula I is selected from a groupconsisting of

wherein n is an integer with value 1-50. In some cases, n is a integerof value 1-10, e.g. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some cases, the compound of Formula I is selected from a groupconsisting of

wherein n is an integer with value 1-50. In some cases, n is a integerof value 1-10, e.g. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some cases, the compound of Formula I is selected from a groupconsisting of

wherein n is an integer with value 1-50. In some cases, n is a integerof value 1-10, e.g. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some cases, the compound of Formula I is selected from a groupconsisting of

wherein n is an integer with value 1-50. In some cases, n is a integerof value 1-10, e.g. n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is selected from a groupconsisting of

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is (E)-2-cyano N (2 (2 (2methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.In some cases, the compound of Formula I is(Z)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.In some cases, the compound of Formula I is(Z)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.In some cases, the compound of Formula I is(Z)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is (E)-2-cyano N (2 (2 (2methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is (E)-1-cyano N (2 (2 (2methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.In some cases, the compound of Formula I is(Z)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.In some cases, the compound of Formula I is(Z)-1-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.In some cases, the compound of Formula I is(Z)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)but-2-enamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.In some cases, the compound of Formula I is(Z)-1-cyano-N-(2,3-dihydroxypropyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)prop-1-ene-1-sulfonamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(R,E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.In some cases, the compound of Formula I is(R,Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)methyl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.

In some cases, the compound of Formula I is:

In some cases, the compound of Formula I is(E)-2-cyano-3-(6-(piperidin-1-yl)naplithalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.In some cases, the compound of Formula I is(Z)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-(((2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.

The disclosure also provides compounds of Formula II:

wherein Ar₂ and each Ar₁ is independently C₁-C₁₄ arylene or C₁-C₁₄heteroarylene, each optionally substituted with one or more R₄₁; whereineach R₄₁ is independently halogen, —CN, —OR₄₂, —NR₄₃R₄₄, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₄₅, R₄₂, R₄₃ and R₄₄ are independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₄₅; eachR₄₅ is independently halogen, —OR₄₆, —NR₄₇R₄₈, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; and R₄₆, R₄₇ and R₄₈ are independently hydrogenor C₁-C₁₀ alkyl;

In some compounds of formula II each of Ar₁ is independently asubstituted or unsubstituted naphthylene or a substituted orunsubstituted phenylene.

In some compounds of Formula I, Ar₂ is a substituted or unsubstitutednaphthylene or a substituted or unsubstituted phenylene.

In some compounds of Formula II, Ar₂ is a substituted or unsubstitutedpyridyl, substituted or unsubstituted pyrimidyl, substituted orunsubstituted pyrazinyl or substituted or unsubstituted pyradizinyl.

In some compounds of Formula II, Ar₂ is a substituted or unsubstitutedpyridyl.

The substituent EDG in Formula II is an electron donating group. In somecompounds of Formula II, EDG is any electron donating group known in theart. In some cases, it is any atom or functional group that is capableof donating some of its electron density into a conjugated pi system viaresonance or inductive electron withdrawal, thus making the pi systemmore nucleophilic. In some compounds of Formula II, the EDG is —OR₄₉,—NR₅₀R₅₁, —SR₅₂, —PR₅₃R₅₄, —NR₅₅C(O)R₅₆, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, heterocycloalkyl, C₁-C₁₀ arylene, orC₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₅₇; wherein each R₅₇ is independently halogen, —OR₅₈,—NR₅₉R₆₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene; each of R₄₉,R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₈, R₅₉ and R₆₀ is independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₆₁ andwherein R₅₀ and R₅₁ are optionally joined together to form aheterocycloalkyl or heteroaryl optionally substituted with R₆₁; each ofR₆₁ is independently halogen, —OR₆₂, —NR₆₃R₆₄, alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₆₅; each of R₆₂, R₆₃ and R₆₄ is independently hydrogenor C₁-C₁₀ alkyl; and each R₆₅ is independently C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene.

In some compounds of formula II, EDG is selected from a group consistingof

In some compounds of formula II, EDG is

In some compounds of formula II, EDG is

The substituent EWG in Formula II is an electron withdrawing group. Insome compounds of Formula II, EWG may be any atom or group that may becapable of drawing electron density from neighboring atoms towardsitself, either by resonance or inductive effects. In some compounds ofFormula II, EWG is halogen, —CN, —NO₂, —SO₃H, —CR₆₆R₆₇R₆₈, —COR₆₉, or—COOR₇₀; wherein each R₆₆, R₆₇ and R₆₈ is independently hydrogen orhalogen; R₆₉ is halogen, hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl,C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₁; R₇₀ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl,C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₂; each R₇₁ and R₇₂ is independently C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene.

In some cases, EWG is selected from a group consisting of —F, —Cl, —Br,—CH═O, NO₂, —CF₃, —CCl₃, —SO₃ and —CN. In some cases, the EWG is —F,—Cl, or —Br. In some cases, the EWG is —CN.

The substituent WSG in Formula II is a water soluble group in somecases. In some compounds of Formula II, WSG is hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₃; wherein each R₇₃ is independently halogen, —OR₇₄,—NR₇₅R₇₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₇₇; each R₇₄,R₇₅ and R₇₆ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl,C₁-C₁₀ cycloalkyl, heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₇; each R₇₇ is independently halogen, —OR₇₈,—NR₇₉R₈₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, —(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl), C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; and each of R₇₈, R₇₉ and R₈₀ is independentlyhydrogen or C₁-C₁₀ alkyl.

The substituent WSG in the Formula II is a water soluble group. In somecompounds, WSG groups serve to alter the solubility of the compounds ofFormula II in aqueous systems. In some cases, WSG is hydrogen, C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₇₃; wherein

each R₇₃ is independently halogen, —OR₇₄, —NR₇₅R₇₆, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, orC₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₇; each R₇₄, R₇₅ and R₇₆ is independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₇₇; each R₇₇is independently halogen, —OR₇₈, —NR₇₉R₈₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; and each of R₇₈, R₇₉ and R₈₀ is independentlyhydrogen or C₁-C₁₀ alkyl.

In some compounds of Formula II, the WSG is hydrogen.

In some compounds of Formula II, the WSG is

In other compounds of Formula II, the WSG is polyethylene glycol,polypropylene glycol, co-polymer of polyethylene glycol andpolypropylene glycol, or alkoxy derivatives thereof. In some compoundsof Formula II, WSG is

wherein n is an integer from 0-50 and R₈₁ is hydrogen, C₁-C₁₀ alkyl, aC₁-C₁₀ alkenyl, or a C₁-C₁₀ alkynyl wherein each wherein the alkyl,alkenyl, or alkynyl is optionally substituted with one or more C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene. In some compounds of FormulaII, R₈₁ is hydrogen. In some compounds of Formula II, R₈₁ is methyl. Insome compounds of Formula II, R₈₁ is ethyl. In some compounds of FormulaII, R₈₁ is CH₂—C≡CH. In some compounds of Formula IIn is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50. In some compounds of Formula IInis an integer of value 1-10, 1-20, 1-30, 1-40, 1-50, 10-20, 10-30,10-40, 10-50, 20-30, 20-40, 20-50, 30-40, 30-50, or 40-50. In somecompounds of Formula II, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In somecompounds of Formula II, n is 0, 3 or 6.

In some cases, the WSG is

wherein each R₈₂ is hydrogen or C₁-C₁₀ alkyl. In some cases each R₈₂ isindependently a hydrogen, methyl, ethyl, propyl, or butyl.

In some cases, the WSG is

In some cases, the WSG is

In some cases, the WSG is

wherein each R₈₃ is hydrogen or C₁-C₁₀ alkyl. In some cases each R₈₃ isindependently a hydrogen, methyl, ethyl, propyl, or butyl.

In some cases, the WSG is

In some cases, the WSG is

In some compounds of Formula II, WSG is —(C₁-C₁₀ alkyl)-R₇₃—R₇₇. In somecompounds of Formula II, WSG is —(C₁-C₁₀ alkyl)-R₇₃—R₇₇ and R₇₃ isC₁-C₁₀ heteroarylene. In some compounds of Formula II, WSG is —(C₁-C₁₀alkyl)-R₇₃—R₇₇, R₇₃ is C₁-C₁₀ heteroarylene and R₇₇ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula II, WSG is —CH₃—R₇₃—R₇₇.

In some compounds of Formula II, WSG is —CH₃—R₇₃—R₇₇ and R₇₃ istriazole, imidazole, or pyrrazole.

In some compounds of Formula II, WSG is —CH₃—R₇₃—R₇₇ and R₇₃ istriazole.

In some compounds of Formula II, WSG is —CH₃—R₇₁—R₇₇ and R₇₃ is1,2,4-triazole.

In some compounds of Formula II, WSG is —CH₃—R₇₃—R₇₇ and R₇₃ is1,2,3-triazole.

In some compounds of Formula II, WSG is —CH₃—R₇₃—R₇₇, R₇₃ is1,2,3-triazole and R₇₇ is —(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula II, WSG is —CH₃—R₇₃—R₇₇, R₇₃ is1,2,3-triazole and R₇₇ is —(C₁alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula II, WSG is —CH₃—R₇₃—R₇₇, R₇₃ is1,2,3-triazole, R₇₇ is —(C₁alkyl)(C₁-C₁₀heretocycloalkyl), andC₁-C₁₀heretocycloalkyl is a tetrahydropyran derivative.

In some compounds of Formula II, WSG is —CH₃—R₇₃—R₇₇, R₇₃ is1,2,3-triazole, and R₇₇ is

In some compounds of Formula II, WSG is

wherein each R₈₇ is hydrogen, C₁-C₁₀ alkyl, or —C(═O)C₁-C₁₀ alkyl. Insome compounds of Formula II, each R₈₇ is independently a hydrogen,methyl, ethyl, propyl, butyl, acetate, propionate, or butyrate. In somecompounds of Formula II, each R₈₇ is independently a hydrogen or methyl.In some compounds of Formula I, each R₈₇ is independently a methyl oracetate.

In some compounds of Formula II, WSG

In some compounds of Formula II, WSG is

In some compounds of Formula II, WSG is —(C₁-C₁₀ heteroalkyl)-R₇₃—R₇₇.In some compounds of Formula II, WSG is —(C₁-C₁₀ heteroalkyl)-R₇₃—R₇₇and R₇₃ is C₁-C₁₀ heteroarylene. In some compounds of Formula II, WSG is—(C₁-C₁₀ heteroalkyl)-R₇₃—R₇₇ and R₇₃ is C₁-C₁₀ heteroarylene and R₇₇ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula II, WSG is

and p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

In some compounds of Formula II, p is an integer of value 1-10, 1-20,1-30, 1-40, 1-50, 10-20, 10-30, 10-40, 10-50, 20-30, 20-40, 20-50,30-40, 30-50, or 40-50.

In some compounds of Formula II, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In some compounds of Formula II, p is 1, 2, 3, 4, 5, or 6. In somecompounds of Formula II, p is 3 or 6.

In some compounds of Formula II, WSG is

and p 3.

In some compounds of Formula II, WSG is

and R₇₃ is a C₁-C₁₀ heteroarylene.

In some compounds of Formula II, WSG is

and R₇₃ is a C₅ heteroarylene.

In some compounds of Formula II, WSG is

and R₇₃ is triazole, imidazole, or pyrrazole.

In some compounds of Formula I II WSG is

and R₇₃ is triazole.

In some compounds of Formula II, WSG is

and R₇₃ is 1, 2, 4-triazole. In some compounds of Formula II, WSG is

and R₇₃ is 1, 2, 3-triazole.

In some compounds of Formula II, WSG is

R₇₃ is 1, 2, 3-triazole, and p is 3.

In some compounds of Formula II, WSG is

R₇₃ is 1,2,3-triazole and R₇₇ is —(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula II, WSG is

R₇₃ is 1,2,3-triazole and R₇₇ is —(C₁alkyl)(C₁-C₁₀heretocycloalkyl).

In some compounds of Formula II, WSG is

R₇₃ is 1,2,3-triazole, R₇₇ is a tetrahydropyran derivative.

In some compounds of Formula II, WSG is

R₇₃ is 1,2,3-triazole, and R₇₇ is

In some compounds of Formula II, WSG is

R₇₃ is 1,2,3-triazole, R₇₇ is

and p is 3.

In some compounds of Formula II, WSG is wherein each R₈₇ is hydrogen,C₁-C₁₀ alkyl, or —C(═O)C₁-C₁₀ alkyl. In some compounds of Formula II,each R₈₇ is independently a hydrogen, methyl, ethyl, propyl, butyl,acetate, propionate, or butyrate. In some compounds of Formula II, eachR₈₇ is independently a hydrogen or methyl. In some compounds of FormulaII, each R₈₇ is independently a methyl or acetate.

In some compounds of Formula II, WSG is

In some compounds of Formula II, WSG is

In some compounds of Formula II, Y is absent, O, NH, or S. In somecompounds of Formula II, Y is absent (i.e. Y is a bond). In somecompounds of Formula II, Y is O. In some compounds of Formula II, Y isNH. In some compounds of Formula II, Y is S.

The variable x in Formula II is an integer from 0-10. In some compoundsof Formula II, x is 0. In some compounds of Formula II, x is 1. In somecompounds of Formula II, x is 2. In some compounds of Formula II, x is3. In some compounds of Formula II, x is 4. In some compounds of FormulaII, x is 5. In some compounds of Formula II, x is 6. In some compoundsof Formula II, x is 7. In some compounds of Formula II, x is 8. In somecompounds of Formula II, x is 9. In some compounds of Formula II, x is10.

The variable y in Formula II is an integer from 0-10. In some compoundsof Formula II, y is 0. In some compounds of Formula II, y is 1. In somecompounds of Formula II, y is 2. In some compounds of Formula II, y is3. In some compounds of Formula II, y is 4. In some compounds of FormulaII, y is 5. In some compounds of Formula II, y is 6. In some compoundsof Formula II, y is 7. In some compounds of Formula II, y is 8. In somecompounds of Formula II, y is 9. In some compounds of Formula II, y is10.

The variable z in Formula II is an integer from 1-10. In some compoundsof Formula II, z is 1. In some compounds of Formula II, z is 2. In somecompounds of Formula II, z is 3. In some compounds of Formula II, z is4. In some compounds of Formula II, z is 5. In some compounds of FormulaII, z is 6. In some compounds of Formula II, z is 7. In some compoundsof Formula II, z is 8. In some compounds of Formula II, z is 9. In somecompounds of Formula II, z is 10.

In some compounds of formula II, x is 0, y is 0, z is 1, and Y is O.

In some compounds of formula II, x is 0, y is 0, z is 1, and Y is S.

In some compounds of formula II, x is 0, y is 0, z is 1, and Y is NH.

In some compounds of formula II, x is 0, y is 0, z is 1, and Y isabsent.

In some compounds of formula II, x is 0, y is 0, z is 2, and Y is O.

In some compounds of formula II, x is 0, y is 0, z is 2, and Y is S.

In some compounds of formula II, x is 0, y is 0, z is 2, and Y is NH.

In some compounds of formula II, x is 0, y is 0, z is 2, and Y isabsent.

In one aspect the disclosure provides a compound of Formula IIa:

wherein EDG, Ar₁, Ar₂, Y, EWG, and WSG are defined as above for FormulaII.

In one aspect the disclosure provides a compound of Formula IIb:

wherein EDG, Ar₁, Ar₂, EWG, and WSG are defined as above for Formula II.

In some cases, the compound according to Formula II is selected from agroup consisting of:

wherein n is an integer with value 0-50. In some compounds of FormulaII, n is a integer of value 0-10, e.g. n is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, or 10.

In some cases the compound of Formula II is selected from a groupconsisting of:

In some cases, the compound of Formula II is selected from a groupconsisting of

wherein R85 is H or CN.

In some cases, the compound of Formula II is selected from a groupconsisting of

wherein R₈₅ is H or CN and R₈₆ is

wherein n is an integer with value 0-50. In some compounds of FormulaII, n is a integer of value 0-10, e.g. n is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, or 10.

In some cases, the compound of Formula II is selected from a groupconsisting of

wherein R₈₅ is H or CN and R₈₆ is H.

In some cases, the compound of Formula II is selected from a groupconsisting of

wherein R₈₅ is H or CN and R₈₆ is

wherein n is an integer with value 0-50. In some compounds of FormulaII, n is a integer of value 0-10, e.g. n is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, or 10.

In some cases the compound of Formula II is:

In some cases the compound of Formula II is2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile.

In some cases the compound of Formula II is:

In some cases the compound of Formula II is4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile.

Routes of Administration

In some cases, the formulations of the present disclosure draw upon manysuitable modes of administration. In some cases, delivery is achievedeither via local or systemic administration. Suitable routes ofadministration include, but are not limited to, oral, intravenous,rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal,transdermal, vaginal, otic, nasal, and topical administration. Inaddition, by way of example only, parenteral delivery includesintramuscular, subcutaneous, intravenous, intramedullary injections, aswell as intrathecal, direct intraventricular, intraperitoneal,intralymphatic, and intranasal injections. In some cases, the compoundsof the disclosure are administered in a systemic manner. In some casesadministration is parenteral. In some cases the administration isintravenous. In some cases the administration is subcutaneous. In somecases the administration is intramuscular. In some cases theadministration is intrathecal. Administration can take place via enteraladministration (absorption of the drug through the gastrointestinaltract) or parenteral administration, for example by injection, infusion,or implantation. In some cases administration is transmucosal, such asoral, buccal, sublingual, nasal, pulmonary, or rectal. In some casesadministration is oral. In some cases administration is buccal. In somecases administration is sublingual. In some cases administration isnasal. In some cases administration is pulmonary. In some casesadministration is rectal. In some cases administration is transdermal.In some cases administration is intradermal. In some casesadministration is topica. In some cases administration is topicalocular.

In certain cases, a compound as described herein is administered in alocal rather than systemic manner, for example, via injection of thecompound directly into an organ, often in a depot preparation orsustained release formulation. In specific cases, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other cases, the drug is delivered in a targeted drugdelivery system, for example, in a liposome coated with organ-specificantibody. In such cases, the liposomes are targeted to and taken upselectively by the organ. In yet other cases, the compound as describedherein is provided in the form of a rapid release formulation, in theform of an extended release formulation, or in the form of anintermediate release formulation. In yet other cases, the compounddescribed herein is administered topically.

In some cases, the compounds are administered to the eye. In some cases,the pharmaceutical composition of the disclosure administered to eye isdelivered to the retina, intraocular space, ocular surface,interconnecting innervation, conjunctiva, lacrimal glands, or meibomianglands. In some cases, the compounds are administered topically to theeye. In some cases, the compounds are administered as an eye drop.

The compounds according to the disclosure are effective over a widedosage range. In some cases, in the treatment of adult humans, dosagesare from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day,and from 5 to 40 mg per day are examples of dosages that are used. Anexemplary dosage is 10 to 30 mg per day. In some cases the effectiveamount the compound corresponds to about 50-500 mg of compound per adultsubject. The exact dosage will depend upon the route of administration,the form in which the compound is administered, the subject to betreated, the body weight of the subject to be treated, and thepreference and experience of the attending physician.

In some cases the effective amount the compound corresponds to about0.01-1000 mg of compound per adult human subject per dosage. In somecases, the effective dose of compound is be 50-500 mg per adult humanper dosage. In some cases the effective amount corresponds to about0.01-100 mg, 0.01-200 mg, 0.01-300 mg, 0.01-400 mg, 0.01-500 mg,0.01-600 mg, 0.01-700 mg, 0.01-800 mg, 0.01-900 mg, 0.01-1000 mg,0.1-100 mg, 0.1-200 mg, 0.1-300 mg, 0.1-400, 0.1-500 mg, 0.1-600 mg,0.1-700 mg, 0.1-800 mg, 0.1-900 mg, 0.1-1000 mg, 1-100 mg, 1-200 mg,1-300 mg, 1-400 mg, 1-500 mg, 1-600 mg, 1-700 mg, 1-800 mg, 1-900 mg,100-200 mg, 100-300 mg, 100-400 mg, 100-500 mg, 100-600 mg, 100-700 mg,100-800 mg, 100-900 mg, 100-1000 mg, 200-300 mg, 200-400 mg, 200-500 mg,200-600 mg, 200-700 mg, 200-800 mg, 200-900 mg, 200-1000 mg, 300-400 mg,300-500 mg, 300-600 mg, 300-700 mg, 300-800 mg, 300-900 mg, 300-1000 mg,400-500 mg, 400-600 mg, 400-700 mg, 400-800 mg, 400-900 mg, 400-1000 mg,500-600 mg, 500-700 mg, 500-800 mg, 500-900 mg, 500-1000 mg, 600-700 mg,600-800 mg, 600-900 mg, 600-1000 mg, 700-800 mg, 700-900 mg, 700-1000mg, 800-900 mg, 800-1000 mg or about 900-1000 mg per adult human perdosage. In some cases, the effective amount corresponds to about 50-100mg, 50-400 mg, 50-500 mg, 100-200 mg, 100-300 mg, 100-400 mg, 100-500mg, 200-300 mg, 200-400 mg, 200-500, 300-400 mg, 300-500 mg, or 400-500mg per adult human per dosage. The exact dosage will depend upon theroute of administration, the form in which the compound is administered,the subject to be treated, the body weight of the subject to be treated,and the preference and experience of the attending physician.

In some cases, a compound of the disclosure is administered in a singledose. In some cases, a compound of the disclosure is administered inmultiple doses. In some cases, dosing is about once, twice, three times,four times, five times, six times, or more than six times per day. Insome cases, dosing is about once a month, once every two weeks, once aweek, or once every other day. In another case a compound of thedisclosure and another agent are administered together about once perday to about 6 times per day. In some cases the administration of acompound of the disclosure and an agent continues for less than about 7days. In yet another case the administration continues for more thanabout 6, 10, 14, 28 days, two months, six months, or one year. In somecases, continuous dosing is achieved and maintained as long asnecessary.

In some cases, administration of the compounds of the disclosurecontinues as long as necessary. In some cases, a compound of thedisclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28days. In some cases, a compound of the disclosure is administered forless than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some cases, a compoundof the disclosure is administered chronically on an ongoing basis, e.g.,for the treatment of chronic effects.

In some cases, for administration to the eyes, compounds areadministered several times a day per eye. In some cases, the compoundsare administered one to ten times, one to four times, or once a day. Insome cases, the compounds are administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 times a day. In some cases, the size of the drop administered is inthe range of about 10-100 μL, about 10-90 μL, about 10-80 μL, about10-70 μL, about 10-60 μL, about 10-50 μL, about 10-40 μL, about 10-30μL, about 20-100 μL, about 20-90 μL, about 20-80 μL, about 20-70 μL,about 20-60 μL, about 20-50 μL, about 20-40 μL, or about 20-30 μL. Oneexample of the disclosure administers a drop in the range of about 10 toabout 30 μL. One example of the disclosure administers a drop in therange of about 10 to about 100 μL. One example of the disclosureadministers a drop in the range of about 20 to about 50 μL. One exampleof the disclosure administers a drop in the range of about 20 to about40 μL. One example of the disclosure administers a drop in the range ofabout 10 to about 60 μL. In some cases, the eye formulations of thedisclosure is administered several drops per time, for example 1-3 dropsper time, 1-3 drops per time, 1-4 drops per time, 1-5 drops per time,1-6 drops per time, 1-7 drops per time, 1-8 drops per time, 1-9 dropsper time, 1-10 drops per time, 3-4 drops per time, 3-5 drops per time,3-6 drops per time, 3-7 drops per time, 3-8 drops per time, 3-9 dropsper time, 3-10 drops per time, 5-6 drops per time, 5-7 drops per time,5-8 drops per time, 5-9 drops per time, 5-10 drops per time, 7-8 dropsper time, 7-9 drops per time or 9-10 drops per time. In one example, theformulations of the disclosure are administered about one drop per timeand 1-6 times per day.

In some cases, the compounds of the disclosure are administered indosages. It is known in the art that due to intersubject variability incompound pharmacokinetics, individualization of dosing regimen isnecessary for optimal therapy. In some cases, dosing for a compound ofthe disclosure is found by routine experimentation in light of theinstant disclosure.

Pharmaceutical Compositions/Formulations

In some cases, the compounds described herein are formulated intopharmaceutical compositions. In some cases, pharmaceutical compositionsare formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any pharmaceuticallyacceptable techniques, carriers, and excipients are used as suitable toformulate the pharmaceutical compositions described herein: Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound ofFormula I or Formula II and a pharmaceutically acceptable diluent(s),excipient(s), or carrier(s). In certain cases, the compounds describedare administered as pharmaceutical compositions in which compounds ofany of Formula I or Formula II, are mixed with other active ingredients,as in combination therapy. In specific cases, the pharmaceuticalcompositions include one or more compounds of any of Formula I orFormula II.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of any of Formula I or Formula II, with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. In certaincases, the pharmaceutical composition facilitates administration of thecompound to an organism. In some cases, practicing the methods oftreatment or use provided herein, therapeutically effective amounts ofcompounds of any of Formula I or Formula I, provided herein areadministered in a pharmaceutical composition to a mammal having adisease or condition to be detected, diagnosed or treated. In specificcases, the mammal is a human. In certain cases, therapeuticallyeffective amounts vary depending on the severity of the disease, the ageand relative health of the subject, the potency of the compound used andother factors. The compounds described herein are used singly or incombination with one or more therapeutic agents as components ofmixtures.

In some cases, one or more compounds of any of Formula I or Formula IIis formulated in an aqueous solution. In specific cases, the aqueoussolution is selected from, by way of example only, a physiologicallycompatible buffer, such as Hank's solution, Ringer's solution, aqueousacetate buffer, aqueous citrate buffer, aqueous carbonate buffer,aqueous phosphate buffer or physiological saline buffer.

In other cases, one or more compound of any of Formula I or Formula IIis formulated for transmucosal administration. In specific cases,transmucosal formulations include penetrants that are appropriate to thebarrier to be permeated. In still other cases wherein the compoundsdescribed herein are formulated for other parenteral injections,appropriate formulations include aqueous or nonaqueous solutions. Inspecific cases, such solutions include physiologically compatiblebuffers and/or excipients.

In some cases, the compounds described herein are formulated for ocularadministration. In some cases, the ocular formulations is liquid (inform of solutions, suspensions, powder for reconstitution, sol to gelsystems), semi solids (ointments and gels), solids (ocular inserts), andintraocular dosage forms (injections, irrigating solutions andimplants).

In another case, compounds described herein are formulated for oraladministration. Compounds described herein, including compounds of anyof Formula I or Formula II, are formulated by combining the activecompounds with, e.g., pharmaceutically acceptable carriers orexcipients. In various cases, the compounds described herein areformulated in oral dosage forms that include, by way of example only,tablets, powders, pills, dragees, capsules, liquids, gels, syrups,elixirs, slurries, suspensions and the like.

In certain cases, pharmaceutical preparations for oral use are obtainedby mixing one or more solid excipient with one or more of the compoundsdescribed herein, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipients are,in particular, fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; cellulose preparations such as: for example,maize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific cases, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In some cases, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific cases,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain cases, therapeutically effective amounts of at least one ofthe compounds described herein are formulated into other oral dosageforms. Oral dosage forms include push-fit capsules made of gelatin, aswell as soft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. In specific cases, push-fit capsules contain theactive ingredients in admixture with one or more filler. Fillersinclude, by way of example only, lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In other cases, soft capsules, contain one or more activecompound that is dissolved or suspended in a suitable liquid. Suitableliquids include, by way of example only, one or more fatty oil, liquidparaffin, or liquid polyethylene glycol. In addition, stabilizers areoptionally added.

In other cases, therapeutically effective amounts of at least one of thecompounds described herein are formulated for buccal or sublingualadministration. Formulations suitable for buccal or sublingualadministration include, by way of example only, tablets, lozenges, orgels. In still other cases, the compounds described herein areformulated for parental injection, including formulations suitable forbolus injection or continuous infusion. In specific cases, formulationsfor injection are presented in unit dosage form (e.g., in ampoules) orin multi-dose containers. Preservatives are, optionally, added to theinjection formulations. In still other cases, the pharmaceuticalcomposition of any of Formula I or Formula II, are formulated in a formsuitable for parenteral injection as a sterile suspensions, solutions oremulsions in oily or aqueous vehicles. Parenteral injection formulationsoptionally contain formulatory agents such as suspending, stabilizingand/or dispersing agents. In specific cases, pharmaceutical formulationsfor parenteral administration include aqueous solutions of the activecompounds in water-soluble form. In additional cases, suspensions of theactive compounds are prepared as appropriate oily injection suspensions.Suitable lipophilic solvents or vehicles for use in the pharmaceuticalcompositions described herein include, by way of example only, fattyoils such as sesame oil, or synthetic fatty acid esters, such as ethyloleate or triglycerides, or liposomes. In certain specific cases,aqueous injection suspensions contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension contains suitablestabilizers or agents which increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.Alternatively, in other cases, the active ingredient is in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

In still other cases, the compounds of any of Formula I or Formula IIare administered topically. The compounds described herein areformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compositions optionallycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

In yet other cases, the compounds of any of Formula I or Formula II areformulated for transdermal administration. In specific cases,transdermal formulations employ transdermal delivery devices andtransdermal delivery patches and can be lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. In various cases, such patches are constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.In additional cases, the transdermal delivery of the compounds of any ofFormula I or Formula II is accomplished by means of iontophoreticpatches and the like. In certain cases, transdermal patches providecontrolled delivery of the compounds of any of Formula I or Formula II.In specific cases, the rate of absorption is slowed by usingrate-controlling membranes or by trapping the compound within a polymermatrix or gel. In alternative cases, absorption enhancers are used toincrease absorption. Absorption enhancers or carriers include absorbablepharmaceutically acceptable solvents that assist passage through theskin. In some cases, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

In other cases, the compounds of any of Formula I or Formula II areformulated for administration by inhalation. Various forms suitable foradministration by inhalation include, but are not limited to, aerosols,mists or powders. Pharmaceutical compositions of any of Formula I orFormula II are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebuliser, with the use of asuitable propellant (e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas). In specific cases, the dosage unit of a pressurizedaerosol is determined by providing a valve to deliver a metered amount.In certain cases, capsules and cartridges of, such as, by way of exampleonly, gelatin for use in an inhaler or insufflator are formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

In still other cases, the compounds of any of Formula I or Formula IIare formulated in rectal compositions such as enemas, rectal gels,rectal foams, rectal aerosols, suppositories, jelly suppositories, orretention enemas, containing conventional suppository bases such ascocoa butter or other glycerides, as well as synthetic polymers such aspolyvinylpyrrolidone, PEG, and the like. In suppository forms of thecompositions, a low-melting wax such as, but not limited to, a mixtureof fatty acid glycerides, optionally in combination with cocoa butter isfirst melted.

In certain cases, pharmaceutical compositions are formulated in anyconventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients are optionally used as suitable. Pharmaceuticalcompositions comprising a compound of any of Formula I or Formula II aremanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound ofany of Formula I or Formula II described herein as an active ingredient.The active ingredient is in free-acid or free-base form, or in apharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these compounds having the same type of activity.All tautomers of the compounds described herein are included within thescope of the compounds presented herein. Additionally, the compoundsdescribed herein encompass unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein. In addition, the pharmaceuticalcompositions optionally include other medicinal or pharmaceuticalagents, carriers, adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure, buffers, and/or other therapeutically valuable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions described herein include liquid solutions or suspensions,solid forms suitable for solution or suspension in a liquid prior touse, or as emulsions. These compositions also optionally contain minoramounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

In some cases, pharmaceutical composition comprising at least onecompound of any of Formula I or Formula II illustratively takes the formof a liquid where the agents are present in solution, in suspension orboth. Typically when the composition is administered as a solution orsuspension a first portion of the agent is present in solution and asecond portion of the agent is present in particulate form, insuspension in a liquid matrix. In some cases, a liquid compositionincludes a gel formulation. In other cases, the liquid composition isaqueous.

In certain cases, useful aqueous suspension contain one or more polymersas suspending agents. Useful polymers include water-soluble polymerssuch as cellulosic polymers, e.g., hydroxypropyl methylcellulose, andwater-insoluble polymers such as cross-linked carboxyl-containingpolymers. Certain pharmaceutical compositions described herein comprisea mucoadhesive polymer, selected for example fromcarboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Useful pharmaceutical compositions also, optionally, includesolubilizing agents to aid in the solubility of a compound of any ofFormula I or Formula II. The term “solubilizing agent” generallyincludes agents that result in formation of a micellar solution or atrue solution of the agent. Certain acceptable nonionic surfactants, forexample polysorbate 80, are useful as solubilizing agents, as canophthalmically acceptable glycols, polyglycols, e.g., polyethyleneglycol 400, and glycol ethers.

Furthermore, useful pharmaceutical compositions optionally include oneor more pH adjusting agents or buffering agents, including acids such asacetic, boric, citric, lactic, phosphoric and hydrochloric acids; basessuch as sodium hydroxide, sodium phosphate, sodium borate, sodiumcitrate, sodium acetate, sodium lactate andtris-hydroxymethylaminomethane; and buffers such as citrate/dextrose,sodium bicarbonate and ammonium chloride. Such acids, bases and buffersare included in an amount required to maintain pH of the composition inan acceptable range.

Additionally, useful compositions also, optionally, include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other useful pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

Still other useful compositions include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other useful compositions include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In some cases, the formulations of the disclosure is packaged inmultidose form or in single dose units. In some cases, the formulationsare packaged in multidose forms. In some cases the formulations arepackaged as single dose from. In some cases of the disclosure singledose packaging of the formulations can offer several advantages overmulti dose packaging including dosage control, increased patientcompliance, improved product labeling, and reduced counterfeiting. Invarious cases single dosage packaging of the formulations of thedisclosure can be in form of vials, ampoules, tubes, bottles, pouches,packettes, syringes or blister packs.

In alternative cases, other delivery systems for hydrophobicpharmaceutical compounds are employed. Liposomes and emulsions areexamples of delivery vehicles or carriers useful herein. In certaincases, organic solvents such as N-methylpyrrolidone are also employed.In additional cases, the compounds described herein are delivered usinga sustained-release system, such as semipermeable matrices of solidhydrophobic polymers containing the therapeutic agent. Varioussustained-release materials are useful herein. In some cases,sustained-release capsules release the compounds for a few weeks up toover 100 days. Depending on the chemical nature and the biologicalstability of the therapeutic reagent, additional strategies for proteinstabilization are employed.

In certain cases, the formulations described herein comprise one or moreantioxidants, metal chelating agents, thiol containing compounds and/orother general stabilizing agents. Examples of such stabilizing agents,include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

In some cases, the concentration of one or more compounds provided inthe pharmaceutical compositions of the present disclosure is less than100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%,0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%,0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%,0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some cases, the concentration of one or more compounds of thedisclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In some cases, the concentration of one or more compounds of thedisclosure is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some cases, the concentration of one or more compounds of thedisclosure is in the range from approximately 0.001% to approximately10%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some cases, the amount of one or more compounds of the disclosure isequal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g,6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g,1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g,0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g,0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g,0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g,0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some cases, the amount of one or more compounds of the disclosure ismore than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g,0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g,0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g,0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g,0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some cases, the amount of one or more compounds of the disclosure isin the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g,0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

Kits/Articles of Manufacture

The disclosure also provides a kit comprising a compound according tothe disclosure. In some cases, the compounds of the disclosure arecontained in a container as formulations. In some cases, the kitcomprises the compounds of the disclosure contained in a container as asterile liquid formulation. In some cases, the compounds are also placedin the containers as a sterile freeze-dried formulation. In some cases,the container is a vial. In some cases, the container is an amber vial.In some cases, the container is capable of protecting light sensitivecompounds or formulation.

In some cases, such kits comprise a carrier, package, or container thatis compartmentalized to receive one or more containers such as vials,tubes, and the like, wherein one or more of the container(s) comprisethe compound of Formula I or Formula II. Suitable containers include,for example, bottles, vials, syringes, and test tubes. The containersare formed from a variety of materials such as glass or plastic. In somecases, the containers are chosen so as to protect, limit or minimize theexposure of the compounds of Formula I or Formula II to light. In somecases, the container is an amber vial.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products Includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes one or more compounds describedherein, optionally in a composition or in combination with another agentas disclosed herein. The container(s) optionally have a sterile accessport (for example the container is an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle). Such kitsoptionally comprising a compound with an identifying description orlabel or instructions relating to its use in the methods describedherein.

In some cases, a kit typically includes one or more additionalcontainers, each with one or more of various materials (such asreagents, optionally in concentrated form, and/or devices) desirablefrom a commercial and user standpoint for use of a compound describedherein. Non-limiting examples of such materials include, but not limitedto, buffers, diluents, filters, needles, syringes; carrier, package,container, vial and/or tube labels listing contents and/or instructionsfor use, and package inserts with instructions for use. A set ofinstructions will also typically be included. A label is optionally onor associated with the container. For example, a label is on a containerwhen letters, numbers or other characters forming the label areattached, molded or etched into the container itself, a label isassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Inaddition, a label is used to indicate that the contents are to be usedfor a specific therapeutic application. In addition, the label indicatesdirections for use of the contents, such as in the methods describedherein. In certain cases, the pharmaceutical composition is presented ina pack or dispenser device which contains one or more unit dosage formscontaining a compound provided herein. The pack for example containsmetal or plastic foil, such as a blister pack. Or, the pack or dispenserdevice is accompanied by instructions for administration. Or, the packor dispenser is accompanied with a notice associated with the containerin form prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some cases, Compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

Methods of Use

In one aspect, the disclosure provides a method for detecting one ormore amyloid or amyloid like proteins comprising contacting a compoundaccording to according to any one of Formula I or II or a pharmaceuticalcomposition thereof with a sample potentially comprising the amyloid oramyloid like protein, wherein in presence of an amyloid or amyloid likeprotein the compound forms a detectable complex, detecting the formationof the detectable complex such that the presence or absence of thedetectable complex correlates with the presence or absence of theamyloid or amyloid like protein.

In some cases, the compounds of the instant disclosure is used fordetecting one or more amyloid or amyloid like protein with highsensitivity. In some cases, the compounds predict the presence and orabsence of a disease with greater than 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99%sensitivity. In some cases the compounds are capable of detecting one ormore amyloid or amyloid like protein with greater than 50%, 51%, 52%,53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%,67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sensitivity. In some cases the compounds arecapable of detecting one or more amyloid or amyloid like protein withgreater than 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sensitivity.

In some cases, the compounds of the instant disclosure are used fordetecting one or more amyloid or amyloid like protein with highspecificity. In some cases, the compounds detect one or more amyloid oramyloid like protein with greater than 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99%specificity. In some cases the compounds are capable of detecting one ormore amyloid or amyloid like protein with greater than 50%, 51%, 52%,53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%,67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% specificity. In some cases the compounds arecapable of detecting one or more amyloid or amyloid like protein withgreater than 99.5%, 99.6%, 99.7%, 99.8% or 99.9% specificity.

In some cases, the compounds of the disclosure are also used fordetecting one or more amyloid or amyloid like protein with both highspecificity and high specificity. In some cases, the compounds arecapable of detecting one or more amyloid or amyloid like protein withgreater than 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%,62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%,76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sensitivity andgreater than 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%,62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%,76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% specificity.

The disclosure also provides a method for treating or preventing one ormore disease or condition comprising administering to a subject in needof treatment an effective amount of a compound to any one of Formula Ior II or a pharmaceutical composition thereof. In some cases, thecompounds of the disclosure are used to treat or prevent diseases orconditions characterized by protein aggregation or protein misfolding.In some cases, the disease or condition is an amyloid-based disease orcondition.

In some cases, the compounds of the instant disclosure are used fortreating or preventing a disease or condition with high sensitivity. Insome cases, the compounds treat or prevent a disease or condition withgreater than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95% or 99% sensitivity. In some cases thecompounds are capable of treating or preventing a disease or conditionwith greater than 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%,61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sensitivity. Insome cases the compounds are capable of treating or preventing a diseaseor condition with greater than 99.5%, 99.6%, 99.7%, 99.8% or 99.9%sensitivity.

In some cases, the compounds of the instant disclosure are used fortreating or preventing a disease or condition with high specificity. Insome cases, the compound predict the presence and or absence of adisease with greater than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% specificity. In somecases the compounds are capable of diagnosis with greater than 50%, 51%,52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%,66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%,80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% specificity. In some cases the compoundsare capable of diagnosis with greater than 99.5%, 99.6%, 99.7%, 99.8% or99.9% specificity.

In some cases, the compounds of the disclosure are also used fortreating or preventing a disease or condition with both high specificityand high specificity. In some cases, the compounds are capable ofdiagnosis with greater than 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sensitivity and greater than 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%,58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%,72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%specificity.

Also provided herein is a method of determining the presence or absenceof one or more disease or condition in a subject comprisingadministering to the subject an effective amount of a compound accordingto any one of Formula I or II or a pharmaceutical composition thereof,wherein in presence of the disease or condition the administeredcompound forms a detectable complex, and detecting the formation of thedetectable complex such that presence or absence of detectable complexcorrelates with the presence or absence of the disease or condition. Insome cases, the compounds of the disclosure are used for determining thepresence or absence of one or more amyloid-based disease or condition,wherein in presence of the amyloid-based disease or condition theadministered compound forms a detectable complex, and detecting theformation of the detectable complex such that presence or absence ofdetectable complex correlates with the presence or absence of theamyloid-based disease or condition. In some cases, the compounds of thedisclosure are used for determining the presence or absence of one ormore disease or condition characterized by protein aggregation orprotein misfolding.

In some cases, the method includes comparing the amount of thedetectable complex to a normal control value, wherein an increase in theamount of the complex compared to a normal control value indicates thatsaid patient is suffering from or is at risk of developing the diseaseor condition.

In some cases a single dose of the compounds of the disclosure is usedto determining the presence or absence of multiple diseases disease orconditions in a subject. In some cases, a single dose is used to detectthe presence or absence of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19 or 20 diseases in a subject. In some cases, a singledose is used to determine the presence of 1, 2, 3, 4, or 5 disease orconditions.

In some cases, the compounds of the instant disclosure are used fordiagnosis with high sensitivity. In some cases, the compounds predictthe presence and or absence of a disease with greater than 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95% or 99% sensitivity. In some cases the compounds are capable ofdiagnosis with greater than 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sensitivity. In some cases the compounds are capable of diagnosis withgreater than 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sensitivity.

In some cases, the compounds of the instant disclosure are used fordiagnosis with high specificity. In some cases, the compounds predictthe presence and or absence of a disease with greater than 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95% or 99% specificity. In some cases the compounds are capable ofdiagnosis with greater than 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%specificity. In some cases the compounds are capable of diagnosis withgreater than 99.5%, 99.6%, 99.7%, 99.8% or 99.9% specificity.

In some cases, the compounds of the disclosure are also used fordiagnosis with both high specificity and high specificity. In somecases, the compounds are capable of diagnosis with greater than 50%,51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%,65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sensitivity and greater than 50%,51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%,65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%,79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% specificity.

Also provided herein is a method of monitoring minimal residual diseasein a patient following treatment with a compound or a mixture accordingto the disclosure. The method includes bringing the sample or a specificbody part or body area suspected to contain the amyloid or amyloid likeprotein into contact with a compound of the disclosure, allowing thecompound to bind to the amyloid or amyloid like protein to form adetectable complex, detecting the formation of the detectable complexand correlating the presence or absence of the detectable complex withthe presence or absence of amyloid or amyloid like protein in the sampleor specific body part or area. In some cases, the method includescomparing the amount of said detectable complex to a normal controlvalue, wherein an increase in the amount of said detectable complexcompared to a normal control value indicates that said patient is stillbe suffering from a minimal residual disease.

Also provided herein is a method of predicting responsiveness of apatient to a treatment, wherein the method includes bringing the sampleor a specific body part or body area suspected to contain the amyloid oramyloid like protein into contact with a compound of the disclosure,allowing the compound to bind to the amyloid or amyloid like protein toform a detectable complex, detecting the formation of the detectablecomplex and correlating the presence or absence of the detectablecomplex with the presence or absence of amyloid or amyloid like proteinin the sample or specific body part or area. In some cases, the methodoptionally includes comparing the amount of the detectable complexbefore and after onset of the treatment, wherein a decrease in theamount of the detectable complex indicates that the patient is beingresponsive to the treatment.

Also provided herein is screening method, wherein the method comprisesadministering to a subject an effective amount of a compound of FormulaI or II, or a pharmaceutical composition thereof. In some cases, uponadministration, the compound of Formula I or II forms a detectablecomplex. In some cases, the method further comprises measuring a signalgenerated by the compound of Formula I or Formula II upon administrationto the subject, or by the detectable complex formed by the compound ofFormula I or II. In some cases, the method also comprises making aclinical decision based on the measured signal.

In some cases, the detection of the detectable complex disclosurecomprises illuminating the sample with light of an appropriatewavelength for a peak region of a fluorescent excitation spectrum forthe detectable complex and detecting light received from the sample ofan appropriate wavelength for a peak region of a fluorescent emissionspectrum for the detectable complex. In some cases, the detectablecomplex is a complex of a compound of Formula I or II with a amyloid oramyloid-like protein. In some cases, the excitation spectrum has a peakat about 200 nm, 210 nm, 220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm,280 nm, 290 nm, 300 nm, 310 nm, 320 nm, 330 nm, 340 nm, 350 nm, 360 nm,370 nm, 380 nm, 390 nm, 400 nm, 410 nm, 420 nm, 430 nm, 440 nm, 450 nm,460 nm, 470 nm, 480 n, 490 nm, 500 nm, 510 nm, 520 nm, 530 nm, 540 nm,560 nm, 570 nm, 580 nm, 590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 640 nm,650 nm, 660 nm, 670 nm, 680 nm, 690 nm, 700 nm, 710 nm, 720 nm, 730 nm,740 nm, 750 nm, 760 nm, 770 nm, 780 nm, 790 nm, 800 nm, 810 nm, 820 nm,830 nm, 840 nm, 850 nm, 860 nm, 870 nm, 880 nm, 890 nm, or 900 nm. Insome cases, the fluorescent excitation spectrum of the detectablecomplex has a peak at about 350-400, 350-450 nm, 350-500 nm, 350-550 nm,350-600 nm, 400-450 nm, 400-500, 400-550 nm, 400-600 nm, 450-500 nm,450-550 nm, 450-600 nm, 500-550, or 550-600 nm. In some cases, thefluorescent excitation spectrum of the detectable complex has a peak atabout 350-400 nm, 400-500 nm or 450-500 nm. In some cases, theilluminating of the sample is at a wavelength within plus or minus about100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, 20 nm, 10 nm,or 0 nm of the peak of the excitation spectrum. In some cases, theilluminating light has a wavelength of 300-500 nm, 350-450 nm, 400-500nm. In some cases, the illuminating light has a wavelength of 400 nm.

In some cases, the emission spectrum has a peak of about 200 nm, 210 nm,220 nm, 230 nm, 240 nm, 250 nm, 260 nm, 270 nm, 280 nm, 290 nm, 300 nm,310 nm, 320 nm, 330 nm, 340 nm, 350 nm, 360 nm, 370 nm, 380 nm, 390 nm,400 nm, 410 nm, 420 nm, 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 n,490 nm, 500 nm, 510 nm, 520 nm, 530 nm, 540 nm, 560 nm, 570 nm, 580 nm,590 nm, 600 nm, 610 nm, 620 nm, 630 nm, 640 nm, 650 nm, 660 nm, 670 nm,680 nm, 690 nm, 700 nm, 710 nm, 720 nm, 730 nm, 740 nm, 750 nm, 760 nm,770 nm, 780 nm, 790 nm, 800 nm, 810 nm, 820 nm, 830 nm, 840 nm, 850 nm,860 nm, 870 nm, 880 nm, 890 nm, or 900 nm. In some cases, the emissionspectrum of the detectable complex has a peak at about 500-550 nm, insome cases at about 510-540 nm. In some cases, the emission spectrum ofthe detectable complex has a peak at about 520 nm, 521 nm, 522 nm, 523nm, 524 nm, 525 nm, 526 nm, 527 nm, 528 nm, 529 nm, 530 nm, 531 nm, 532nm, 533 nm, 534 nm, 535 nm, 536 nm, 537 nm, 538 nm, 539 nm or 540 nm. Insome cases, the detecting of light received from the sample is at awavelength within plus or minus about 100 nm, 90 nm, 80 nm, 70 nm, 60nm, 50 nm, 40 nm, 30 nm, 20 nm, 10 nm, or 0 nm of the peak of theemission spectrum.

In some cases, the term amyloid-based disease or condition refers to anydisease or condition. The term also includes any disease or conditioncharacterized by protein aggregation or protein misfolding. In somecases, amyloid-based disease or condition is any disease or conditionthat is associated with the increased or decreased presence of amyloidor amyloid like proteins or proteins, such as the presence of amyloidplaques. In some cases the amyloid based disease or condition is aneuronal disease or condition, for example, neurodegenerative diseases,in which amyloid-beta peptides, oligomers, fibrils, or plaques areimplicated. Non limiting examples of amyloid-based neurodegenerativediseases include Alzheimer's disease, Parkinson's disease, Huntington'sdisease, Down's Syndrome, and spongiform encephalopathies such as, forexample, bovine spongiform encephalopathy (mad cow disease), kuru,Creutzfeldt-Jakob disease, and fatal familial insomnia. In some cases,other amyloid based diseases that are detected, treated or prevented bythe methods of the disclosure include reactive systemic amyloidosis,senile systemic amyloidosis (SAA), familial amyloid polyneuropathy(FAP), familial amyloid cardiomyopathy (FAC), prion disease, coronaryheart disease, atherosclerosis, cerebral hemorrhage, AL amyloidosis,type 2 diabetes, diseases or conditions characterized by a loss ofcognitive memory capacity such as, for example, mild cognitiveimpairment (MCI), Lewy body dementia (LBD), hereditary cerebralhemorrhage with amyloidosis (Dutch type) and the Guam Parkinson-Dementiacomplex. Other diseases which are based on or associated withamyloid-like proteins are progressive supranuclear palsy, multiplesclerosis, HIV-related dementia, ALS (amyotropic lateral sclerosis),inclusion-body myositis (IBM), Adult Onset Diabetes; endocrine tumors,and other diseases, including amyloid-associated ocular diseases thattarget different tissues of the eye, such as the visual cortex,including cortical visual deficits; the anterior chamber and the opticnerve, including glaucoma; the lens, including cataract due tobeta-amyloid deposition; the vitreous, including ocular amyloidosis; theretina, including primary retinal degenerations and maculardegeneration, in particular age-related macular degeneration; the opticnerve, including optic nerve drusen, optic neuropathy and opticneuritis; and the cornea, including lattice dystrophy.

In some cases the compounds of the present disclosure can be employedfor the treatment of Alzheimer's disease, Alzheimer's disease (AD),Parkinson's disease, Huntington's disease, amyotrophic, lateralsclerosis (ALS), Lewy body dementia (LBD), or Down's syndrome. In somecases, the compounds of the present disclosure can be employed for thedetection, diagnosis, treatment and monitoring of Alzheimer's disease.Or the compounds of the present disclosure can be employed for thedetection, diagnosis, treatment and monitoring of Creutzfeldt-Jakobdisease (CJD).

In some cases, amyloid-based diseases or conditions also include oculardiseases associated with pathological abnormalities/changes in thetissues of the visual system, particularly associated withamyloid-beta-related pathological abnormalities/changes in the tissuesof the visual system, such as, for example, neuronal degradation. Insome cases, said pathological abnormalities occur in different tissuesof the eye, such as the visual cortex leading to cortical visualdeficits; the anterior chamber and the optic nerve leading to glaucoma;the lens leading to cataract due to beta-amyloid deposition; thevitreous leading to ocular amyloidosis; the retina leading to primaryretinal degeneration and macular degeneration, for example age-relatedmacular degeneration; the optic nerve leading to optic nerve drusen,optic neuropathy and optic neuritis; and the cornea leading to latticedystrophy.

In some cases, the amyloid or amyloid like proteins and/or proteins thatare detected using the methods of the disclosure include amyloid betapeptides (Aβ), prion peptide (PrP), alpha-synuclein, TAPP (amylin),huntingtin, calcitonin (ACal), atrial natriuretic factor (AANF),apolipoprotein A1 (ApoA1), scrum amyloid A (SAA), mcdin (AMed),prolactin (APro), transthyretin (ATTR), lysozyme (ALys), beta 2microglobulin (Aβ2M), gelsolin (AGel), keratoepithelin (Aker), cystatin(ACys), immunoglobulin light chain AL (AL), S-IBM or superoxidedismutase. In some cases, the amyloid peptide detected by the method ofthe disclosure is Aβ peptide, prion peptide, alpha-synuclein, orsuperoxide dismutase.

In some cases, the subjects for the methods of the instant disclosureare any mammal. In some cases, the subject is a primate (such as ahuman), canine, feline, ovine, bovine and the like. In some cases,biological samples that are used in the diagnosis of anamyloid-associated disease or condition for diagnosing a predispositionto an amyloid-associated disease or condition or for monitoring minimalresidual disease in a patient or for predicting responsiveness of apatient to a treatment with a compound or a composition or a mixtureaccording to the disclosure and as described herein before are, forexample, fluids such as serum, plasma, saliva, gastric secretions,mucus, cerebrospinal fluid, lymphatic fluid, and the like, or tissue orcell samples obtained from an organism such as neural, brain, cardiac orvascular tissue. For determining the presence or absence of the amyloidor amyloid like protein in a sample any immunoassay known to those ofordinary skill in the art may be used such as, for example, assays whichutilize indirect detection methods using secondary reagents fordetection, ELISA's and immunoprecipitation and agglutination assays.

EMBODIMENTS

Specific embodiments of the subject matter disclosed herein is set forthin the following embodiments.

Embodiment P1

A compound of Formula I

wherein EDG is an electron donating group; each Ar is independentlyC₁-C₁₄ arylene or C₁-C₁₄ heteroarylene, each optionally substituted withone more R₁; each R₁ is independently halogen, —OR₂, —NR₃R₄, C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₅; R₂, R₃ and R₄ are independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₅; eachR₅ is independently halogen, —OR₆, —NR₇R₈, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; R₆, R₇, R₈ and R₈₄ are independently hydrogenor C₁-C₁₀ alkyl; EWG is an electron withdrawing group; WSG is a watersoluble group; X is C═O or SO₂; Y is NH, or S; each w is independentlyan integer from 1-5; each x is independently an integer from 0-10; eachy is independently an integer from 0-10; and z is an integer from 1-10.

Embodiment P2

The compound of embodiment P1, wherein EDG is —OR₉, —NR₁₀R₁₁, —SR₁₂,—PR₁₃R₁₄, —NR₁₅C(O)R₁₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₁₇; each R₁₇ is independently halogen, —OR₁₈,—NR₁₉R₂₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene; each of R₉,R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₈, R₁₉ and R₂₀ is independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₂₁ andwherein R₁₀ and R₁₁ are optionally joined together to form aheterocycloalkyl or heteroaryl optionally substituted with R₂₁; each ofR₂₁ is independently halogen, —OR₂₂, —NR₂₃R₂₄, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₂₅; each of R₂₂, R₂₃ and R₂₄ is independently hydrogenor C₁-C₁₀ alkyl; and each R₂₅ is independently C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene.

Embodiment P3

The compound of embodiment P1, wherein EDG is selected from a groupconsisting of

Embodiment P4

The compound of embodiment P1, wherein EDG is

Embodiment P5

The compound of embodiment P1, wherein EWG is halogen, —CN, —NO₂, —SO₃H,—CR₂₆R₂₇R₂₈, —COR₂₉, or —COOR₃₀; each R₂₆, R₂₇ and R₂₈ is independentlyhydrogen or halogen; R₂₉ is halogen, hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, orC₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₁; R₃₀ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl,C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₂; and each R₃₁ and R₃₂ is independently C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene.

Embodiment P6

The compound of embodiment P1, wherein EWG is selected from a groupconsisting of —F, —Cl, —Br, —C═O, NO₂, —CF₃, —CCl₃, —SO₃ and —CN.

Embodiment P7

The compound of embodiment P6, wherein EWG is —CN.

Embodiment P8

The compound of embodiment P1, wherein WSG is hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₃₃; each R₃₃ is independently halogen,—OR₃₄, —NR₃₅R₃₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₇; each R₃₄,R₃₅ and R₃₆ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl,C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₇; each R₃₇ is independently halogen, —OR₃₈,—NR₃₉R₄₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene; and each ofR₃₈, R₃₉ and R₄₀ is independently hydrogen or C₁-C₁₀ alkyl.

Embodiment P9

The compound of embodiment P8, wherein WSG is

Embodiment P10

The compound of embodiment P1, wherein WSG comprises polyethyleneglycol, polypropylene glycol, co-polymer of polyethylene glycol andpolypropylene glycol, or alkoxy derivatives thereof.

Embodiment P11

The compound of embodiment P10, wherein WSG is

wherein n is an integer from 1-50 and R₈₁ is hydrogen, a C₁-C₁₀ alkyl, aC₁-C₁₀ alkenyl, or a C₁-C₁₀ alkynyl wherein each wherein the alkyl,alkenyl, or alkynyl is optionally substituted with one or more C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene.

Embodiment P12

The compound of embodiment P11, wherein R₈₁ is methyl.

Embodiment P13

The compound of embodiment P11, wherein R₈₁ is CH₂—C≡CH.

Embodiment P14

The compound of embodiment P11, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9,or 10.

Embodiment P15

The compound of embodiment P11, wherein n is 3 or 6.

Embodiment P16

The compound of embodiment P8, wherein the WSG is

Embodiment P17

The compound of embodiment P16, wherein the WSG is

Embodiment P18

The compound of embodiment P8, wherein the WSG is

Embodiment P19

The compound of embodiment P18, wherein the WSG is

Embodiment P20

The compound of embodiment P1, wherein R₈₄ is hydrogen.

Embodiment P21

The compound of embodiment P1, wherein R₈₄ is methyl.

Embodiment P22

The compound of embodiment P1, wherein the compound is

selected from a group consisting of wherein n is an integer with value1-10.

Embodiment P23

The compound of embodiment P1, wherein the compound is selected from agroup consisting of

Embodiment P24

The compound of embodiment P1, wherein the compound is

Embodiment P25

The compound of embodiment P1, wherein the compound is

Embodiment P26

The compound of embodiment P1, wherein the compound is

Embodiment P27

The compound of embodiment P1, wherein the compound is

Embodiment P28

The compound of embodiment P1, wherein the compound is

Embodiment P29

The compound of embodiment P28, wherein the compound is

Embodiment P30

The compound of embodiment P1, wherein the compound is

Embodiment P31

The compound of embodiment P30, wherein the compound is

Embodiment P32

The compound of embodiment P1, wherein the compound is

Embodiment P33

The compound of embodiment P1, wherein the compound is

Embodiment P34

The compound of embodiment P1, wherein the compound is

Embodiment P35

The compound of embodiment P1, wherein the compound is

Embodiment P36

The compound of embodiment P1, wherein the compound is

Embodiment P37

The compound of embodiment P1, wherein the compound is

Embodiment P38

The compound of embodiment P1, wherein the compound is

Embodiment P39

The compound of embodiment P1, wherein the compound is

Embodiment P40

A compound of Formula II

(Formula II), wherein EDG is an electron donating group; Ar₂ and eachAr₁ is independently C₁-C₁₄ arylene or C₁-C₁₄ heteroarylene, eachoptionally substituted with one more R₄₁; each R₄₁ is independentlyhalogen, —OR₄₂, —CN, —NR₄₃R₄₄, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₄₅; R₄₂, R₄₃ and R₄₄ are independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₄₅; eachR₄₅ is independently halogen, —OR₄₆, —NR₄₇R₄₈, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; R₄₆, R₄₇ and R₄₈ are independently hydrogen orC₁-C₁₀ alkyl; EWG is an electron withdrawing group; Y is absent, O, NH,or S; WSG is hydrogen or a water soluble group; x is an integer from0-10; y is an integer from 0-10; and z is an integer from 1-10.

Embodiment P41

The compound of embodiment P40, wherein EDG is OR₄₉, NR₅₀R₅₁, —SR₅₂,—PR₅₃R₅₄, —NR₅₅C(O)R₅₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₅₇; each R₅₇ is independently halogen, —OR₅₈,—NR₅₉R₆₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene; each of R₄₉,R₅₀, R₅₁, R₅₂, R₅₁, R₅₄, R₅₅, R₅₆, R₅₈, R₅₉ and R₆₀ is independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₆₁ andwherein R₅₀ and R₅₁ are optionally joined together to form aheterocycloalkyl or heteroaryl optionally substituted with R₆₁; each ofR₆₁ is independently halogen, —OR₆₂, —NR₆₃R₆₄, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₆₅; each of R₆₂, R₆₃ and R₆₄ is independently hydrogenor C₁-C₁₀ alkyl; and each R₆₅ is independently C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene.

Embodiment P42

The compound of embodiment P40, wherein EDG is

Embodiment P43

The compound of embodiment P40, wherein EDG is

Embodiment P44

The compound of embodiment P40, wherein EWG is halogen, —CN, —NO₂,—SO₃H, —CR₆₆R₆₇R₆₈, COR₆₉, or COOR₇₀; each R₆₆, R₆₇ and R₆₈ isindependently hydrogen or halogen; R₆₉ is halogen, hydrogen, C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₇₁; R₇₀ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, heterocycloalkyl, C₁-C₁₀ arylene, orC₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₂; and each R₇₁ and R₇₂ is independently C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,arylene, or C₁-C₁₀ heteroarylene.

Embodiment P45

The compound of embodiment P40, wherein EWG is selected from a groupconsisting of F, Cl, Br, —C═O, NO₂, —CF₃, —CCl₃, —SO₃ and —CN.

Embodiment P46

The compound of embodiment P45, wherein EWG is —CN.

Embodiment P47

The compound of embodiment P40, wherein Y is absent.

Embodiment P48

The compound of embodiment P40, wherein WSG is hydrogen, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₇₃; each R₇₃ is independently halogen,—OR₇₄, —NR₇₅R₇₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene,wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene,or heteroarylene is optionally substituted with one or more R₇₇; eachR₇₄, R₇₅ and R₇₆ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₇; each R₇₇ is independently halogen, —OR₇₈,—NR₇₉R₈₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene; and each ofR₇₈, R₇₉ and R₈₀ is independently hydrogen or C₁-C₁₀ alkyl.

Embodiment P49

The compound of embodiment P48, wherein WSG is hydrogen.

Embodiment P50

The compound of embodiment P48, wherein WSG is

Embodiment P51

The compound of embodiment P40 wherein WSG is polyethylene glycol,polypropylene glycol, co-polymer of polyethylene glycol andpolypropylene glycol, or alkoxy derivatives thereof.

Embodiment P52

The compound of embodiment P51, wherein WSG is

wherein n is an integer from 0-50 and R₈₁ is H, a C₁-C₁₀ alkyl, a C₁-C₁₀alkenyl, or a C₁-C₁₀ alkynyl wherein each wherein the alkyl, alkenyl, oralkynyl is optionally substituted with one or more C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, heterocycloalkyl, C₁-C₁₀ arylene, orC₁-C₁₀ heteroarylene.

Embodiment P53

The compound of embodiment P52, wherein R₈₁ is methyl.

Embodiment P54

The compound of embodiment P52, wherein R₈₁ is CH₂—C≡CH.

Embodiment P55

The compound of embodiment P52, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, or 10.

Embodiment P56

The compound of embodiment P52, wherein n is 3 or 6.

Embodiment P57

The compound of embodiment P48, wherein the WSG is

Embodiment P58

The compound of embodiment P57, wherein the WSG is

Embodiment P59

The compound of embodiment P48, wherein the WSG is

Embodiment P60

The compound of embodiment P59, wherein the WSG is

Embodiment P61

The compound of embodiment P40, wherein each of Ar₁ is independently anaphthalene or a phenylene.

Embodiment P62

The compound of embodiment P40, wherein Ar₂ is naphthalene or aphenylene.

Embodiment P63

The compound of embodiment P40, wherein the compound is selected from agroup consisting of

wherein n is an integer with value 0-10.

Embodiment P64

The compound of embodiment P40, wherein the compound is selected from agroup consisting of

Embodiment P65

The compound of embodiment P40, wherein the compound is

Embodiment P66

The compound of embodiment P40, wherein the compound is

Embodiment P67

The compound of embodiment P40, wherein the compound is

Embodiment P68

The compound of embodiment P40, wherein the compound is

Embodiment P69

A pharmaceutical composition comprising a compound according to any oneof embodiments P1-P66.

Embodiment P70

A pharmaceutical composition of embodiment P69, further comprising oneor more pharmaceutically acceptable additive, carrier or excipientselected from a group consisting of ethanol, DMSO, polyethylene glycol,polypropylene glycol, aqueous acetate buffers, aqueous citrate buffers,aqueous phosphate buffers, aqueous carbonate buffers, cyclodextrins,corn oil, vitamin E, polysorbates, solutol and bile acids.

Embodiment P71

A composition comprising a compound according to any one of embodimentsP1-P66 and an amyloid or amyloid like protein.

Embodiment P72

The composition of embodiment P71, wherein the amyloid or amyloid likeprotein is Aβ peptide, prion peptide, alpha-synuclein, or superoxidedismutase.

Embodiment P73

A method of detecting an amyloid or amyloid like protein comprising: a)contacting a compound according to any one of embodiments P1-P66 with asample potentially comprising the amyloid or amyloid like protein,wherein in presence of an amyloid or amyloid like protein the compoundforms a detectable complex; and b) detecting the formation of thedetectable complex such that the presence or absence of the detectablecomplex correlates with the presence or absence of the amyloid oramyloid like protein.

Embodiment P74

The method of embodiment P73, wherein the detection of the formation ofthe detectable complex is performed by measuring a signal generated bythe detectable complex.

Embodiment P75

The method of embodiment P74, wherein the signal generated by thedetectable complex is an electromagnetic signal.

Embodiment P76

The method of embodiment P74, wherein the electromagnetic signal is afluorescence signal.

Embodiment P77

The method of embodiment P76, wherein the fluorescence signal ismeasures at a wavelength of 450-650 nm.

Embodiment P78

The method of embodiment P76, wherein the fluorescence signal ismeasures at a wavelength of 520-540 nm.

Embodiment P79

The method of embodiment P73, wherein the amyloid or amyloid likeprotein is Aβ peptide, prion peptide, alpha-synuclein, or superoxidedismutase.

Embodiment P80

The method of embodiment P73, wherein the amyloid or amyloid likeprotein is beta amyloid (1-42) (Aβ (1-42)).

Embodiment P81

The method of embodiment P73, wherein the detection of the formation ofthe detectable complex is performed within about 1 sec, about 5 sec,about 1 min, about 10 min, about 30 min or about 60 min of thecontacting of the compound according to any one of embodiments P1-P66with the sample.

Embodiment P82

The method of embodiment P73, wherein the detection of the formation ofthe detectable complex is performed within about 1-5 minutes of thecontacting of the compound according to any one of embodiments P1-P66with the sample.

Embodiment P83

A method of determining the presence or absence of one or more diseaseor condition in a subject comprising: a) administering to the subject aneffective amount of a compound according to any one of embodimentsP1-P66 or a pharmaceutical composition thereof, wherein in presence ofthe disease or condition the administered compound forms a detectablecomplex; and b) detecting the formation of the detectable complex suchthat presence or absence of detectable complex correlates with thepresence or absence of the disease or condition.

Embodiment P84

The method of embodiment P83, wherein the disease or condition ischaracterized by protein aggregation or protein misfolding.

Embodiment P85

The method of embodiment P83, wherein the disease or condition is anamyloid based disease or condition.

Embodiment P86

The method of embodiment P83, wherein the disease or condition isAlzheimer's disease (AD), Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), or Down'ssyndrome.

Embodiment P87

The method of embodiment P83, wherein the disease of condition isAlzheimer's disease.

Embodiment P88

The method of embodiment P83, wherein the disease or condition is aprion disease or condition.

Embodiment P89

The method of embodiment P88, wherein the prion disease or condition isCreutzfeldt-Jakob disease (CJD).

Embodiment P90

The method of embodiment P83, wherein the administering is to the eye ofthe subject.

Embodiment P91

The method of embodiment P83, wherein the administering is systemic ortopical administration.

Embodiment P92

The method of embodiment P83, wherein the detection of the formation ofthe detectable is performed within about 1 sec, about 5 sec, about 1min, about 10 min, about 30 min or about 60 min of the administration ofthe compound according to any one of embodiments P1-P66 to the subject.

Embodiment P93

The method of embodiment P83, wherein the detection of the formation ofthe detectable complex is performed within about 1-5 min of theadministration of the compound according to any one of embodimentsP1-P66 to the subject.

Embodiment P94

The method of embodiment P83, wherein the effective amount the compoundcorresponds to about 50-500 mg of compound per adult human subject.

Embodiment P95

The method of embodiment P83, wherein the detection of the formation ofthe detectable complex is performed by measuring a signal generated bythe detectable complex.

Embodiment P96

The method of embodiment P95, the signal generated by the detectablecomplex is an electromagnetic signal.

Embodiment P97

The method of embodiment P96, wherein the electromagnetic signal is afluorescence signal.

Embodiment P98

The method of embodiment P97, wherein the fluorescence signal ismeasures at a wavelength of 450-650 nm.

Embodiment P99

The method of embodiment P97, wherein the fluorescence signal ismeasures at a wavelength of 520-540 nm.

Embodiment P100

A method of treating or preventing a one or more disease or conditioncomprising administering to a subject in need of treatment an effectiveamount of a compound according to any one of embodiments P1-P66 or apharmaceutical composition thereof.

Embodiment P101

The method of embodiment P100, wherein the disease or condition ischaracterized by protein aggregation or protein misfolding,

Embodiment P102

The method of embodiment P100, wherein the disease or condition is anamyloid based disease or condition.

Embodiment P103

The method of embodiment P100, wherein the disease or condition isAlzheimer's disease (AD), Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), or Down'ssyndrome.

Embodiment P104

The method of embodiment P103, wherein the neurological disorder isAlzheimer's disease.

Embodiment P105

The method of embodiment P100, wherein the disease or condition is aprion disease or condition.

Embodiment P106

The method of embodiment P105, wherein the prion disease or condition isCreutzfeldt-Jakob disease.

Embodiment P107

The method of embodiment P100, wherein effective amount the compoundcorresponds to about 50-500 mg.

Embodiment P108

A screening method comprising administering to a subject an effectiveamount of a compound according to any one of embodiments P1-P66 or apharmaceutical composition thereof, wherein upon administration the acompound according to any one of embodiments P1-P66 may form adetectable complex.

Embodiment P109

The screening method of embodiment P108, further comprising measuring asignal generated by the by the detectable complex or by the compound,according to any one of embodiments P1-P66, administered to the subject.

Embodiment P110

The screening method of embodiment P109, further comprising making aclinical decision based on the measured signal.

Embodiment P111

The screening method of embodiment P109, wherein the signal is anelectromagnetic signal.

Embodiment P112

The screening method of embodiment P111, wherein the electromagneticsignal is a fluorescence signal.

Embodiment P113

The method of embodiment P112, wherein the fluorescence signal ismeasures at a wavelength of 450-650 nm.

Embodiment P114

The method of embodiment P112, wherein the fluorescence signal ismeasures at a wavelength of 520-540 nm.

Embodiment P115

The screening method of embodiment P108, wherein the said administeringis to the eye of the subject.

Embodiment P116

The screening method of embodiment P108, wherein the said administeringis systemic or topical administration.

Embodiment P117

A kit for comprising a compound according to any one of embodimentsP1-P66.

Embodiment 118

The kit of embodiment P117, further comprising instructions for a) usingthe compound for the binding to an amyloid or amyloid like protein toform a detectable complex; and b) detecting the formation of thedetectable complex such that presence or absence of detectable complexcorrelates with the presence or absence of the amyloid or amyloid likeprotein.

Embodiment P119

The kit of embodiment P117, further comprising instructions for a) usingthe compound for binding to an amyloid or amyloid like protein to form adetectable complex; and b) detecting changes in abundance of thedetectable complex over time such that the changes in the abundance ofthe detectable complex over time are correlated to changes in abundanceof amyloid or amyloid like protein over time.

Embodiment P120

The kit of embodiment P119, further comprising instructions forcorrelating the changes in the abundance of the detectable complex tomonitor progression of a disease.

Embodiment P121

The kit of embodiment P117, the compound according to any one ofembodiments P1-P66 is contained in a container as a sterile liquidformulation.

Embodiment P122

The kit of embodiment P117, the compound according to any one ofembodiments P1-P66 is contained in a container as a sterile freeze-driedformulation.

Embodiment P123

The kit of embodiment P120 or P122, wherein the container a vial, forexample an amber vial.

Embodiment P124

The kit of embodiment P120 or P122, wherein the container is capable ofprotecting light sensitive compounds or formulation.

Further embodiments are provided as follows.

Embodiment 1

A compound of Formula I

wherein EDG is an electron donating group; each Ar is independentlyC₁-C₁₄ arylene or C₁-C₁₄ heteroarylene, each optionally substituted withone or more R₁; each R₁ is independently halogen, —OR₂, —NR₃R₄, C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₅; R₂, R₃ and R₄ are independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₅; eachR₅ is independently halogen, —OR₆, —NR₇R₈, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; R₆, R₇, R₈ and R₈₄ are independently hydrogenor C₁-C₁₀ alkyl; EWG is an electron withdrawing group; WSG is a watersoluble group; X is C═O or SO₂; Y is NH, or S; each w is independentlyan integer from 1-5; each x is independently an integer from 0-10; eachy is independently an integer from 0-10; and z is an integer from 1-10.

Embodiment 2

The compound of embodiment 1, wherein EDG is —OR₉, —NR₁₀R₁₁, —SR₁₂,—PR₁₃R₁₄, —NR₁₅C(O)R₁₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₁₇; each R₁₇ is independently halogen, —OR_(B),—NR₁₉R₂₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene; each of R₉,R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₈, R₁₉ and R₂₀ is independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₂₁ andwherein R₁₀ and R₁₁ are optionally joined together to form aheterocycloalkyl or heteroaryl optionally substituted with R₂₁; each ofR₂₁ is independently halogen, —OR₂₂, —NR₂₃R₂₄, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₂₅; each of R₂₂, R₂₃ and R₂₄ is independently hydrogenor C₁-C₁₀ alkyl; and each R₂₅ is independently C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene.

Embodiment 3

The compound of any one of embodiments 1 or 2, wherein EDG is selectedfrom a group consisting of

Embodiment 4

The compound of any one of embodiments 1-3, wherein EDG is

Embodiment 5

The compound of any one of embodiments 1-4, wherein EWG is halogen, —CN,—NO₂, —CR₂₆R₂₇R₂₈, —COR₂₉, or —COOR₃₀; each R₂₆, R₂₇ and R₂₈ isindependently hydrogen or halogen; R₂₉ is halogen, hydrogen, C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₃₁; R₃₀ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₂; and each R₃₁ and R₃₂ is independently C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene.

Embodiment 6

The compound of any one of embodiments 1-5, wherein EWG is selected froma group consisting of —F, —Cl, —Br, —CH═O, NO₂, —CF₃, —CCl₃, —SO₃ and—CN.

Embodiment 7

The compound of embodiment 6, wherein EWG is —CN.

Embodiment 8

The compound of any one of embodiments 1-7, wherein WSG is hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₃; each R₃₃is independently halogen, —OR₃₄, —NR₃₅R₃₆, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₇; each R₃₄, R₃₅ and R₃₆ is independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₇; each R₃₇is independently halogen, —OR₃₈, —NR₃₉R₄₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl), C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene; and each of R₃₈, R₃₉ and R₄₀ is independently hydrogen orC₁-C₁₀ alkyl.

Embodiment 9

The compound of any one of embodiments 1-8, wherein WSG is hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₃; each R₃₃is independently halogen, —OR₃₄, —NR₃₅R₃₆, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₃₇; each R₃₄, R₃₅ and R₃₆ is independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₃₇; each R₃₇is independently halogen, —OR₃₈, —NR₃₉R₄₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; and each of R₃₈, R₃₉ and R₄₀ is independentlyhydrogen or C₁-C₁₀ alkyl.

Embodiment 10

The compound of any one of embodiments 1-9, wherein WSG is

Embodiment 11

The compound of any one of embodiments 1-9, wherein WSG is polyethyleneglycol, polypropylene glycol, co-polymer of polyethylene glycol andpolypropylene glycol, or alkoxy derivatives thereof.

Embodiment 12

The compound of embodiment 11, wherein WSG is

wherein n is an integer from 1-50 and R₈₁ is hydrogen, a C₁-C₁₀ alkyl, aC₁-C₁₀ alkenyl, or a C₁-C₁₀ alkynyl wherein each wherein the alkyl,alkenyl, or alkynyl is optionally substituted with one or more C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene.

Embodiment 13

The compound of any one of embodiments 11 to 12, wherein R₈₁ is methyl.

Embodiment 14

The compound of any one of embodiments 11 to 12, wherein R₈₁ isCH₂—C≡CH.

Embodiment 15

The compound of any one of embodiments 11-14, wherein n is 1, 2, 3, 4,5, 6, 7, 8, 9, or 10.

Embodiment 16

The compound of any one of embodiments 11-15, wherein n is 3 or 6.

Embodiment 17

The compound of any one of embodiments 1-9, wherein the WSG is

Embodiment 18

The compound of embodiment 17, wherein the WSG is

Embodiment 19

The compound of any one of embodiments 1-9, wherein the WSG is

Embodiment 20

The compound of embodiment 19, wherein the WSG is

Embodiment 21

The compound of any one of embodiments 1-8, wherein WSG is —(C₁-C₁₀alkyl)-R₃₃—R₃₇, wherein: R³³ is C₁-C₁₀ heteroarylene; and R₃₇ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

Embodiment 22

The compound of embodiment 21, wherein WSG is —CH₃—R₃₃—R₃₇.

Embodiment 23

The compound of any one of embodiments 21 or 22, wherein R₃₃ is atriazole.

Embodiment 24

The compound of any of embodiments 21-23, wherein R₃₇ is

Embodiment 25

The compound of embodiment 8, wherein the WSG is

Embodiment 26

The compound of embodiment 25, wherein the WSG is

Embodiment 27

The compound of any one of embodiments 1-8, wherein WSG is —(C₁-C₁₀heteroalkyl)-R₃₃—R₃₇, wherein: R₃₃ is C₁-C₁₀ heteroarylene; and R₃₇ is—(C₁-C₆alkyl)(C₁-C₁₀heretocycloalkyl).

Embodiment 28

The compound of embodiment 27, wherein WSG is

and p is 1, 2, 3, 4, 5, or 6.

Embodiment 29

The compound of embodiment 28, wherein p is 3.

Embodiment 30

The compound of any one of embodiments 27-29, wherein R₃₃ is a triazole.

Embodiment 31

The compound of any one of embodiments 27-30, wherein R₃₇ is

Embodiment 32

The compound of any one of embodiments 27-31, wherein WSG is

Embodiment 33

The compound of embodiment 32, wherein WSG is

Embodiment 34

The compound of any one of embodiments 1-33, wherein R₈₄ is hydrogen.

Embodiment 35

The compound of any one of embodiments 1-34, wherein R₈₄ is methyl.

Embodiment 36

The compound of any one of embodiments 1-35, wherein the compound ofFormula (T) is of formula (Ic):

Embodiment 37

The compound of any one of embodiments 1-36, wherein the compound offormula (I) is of formula (Id):

Embodiment 38

The compound of any one of embodiments 1-36, wherein the compound offormula (I) is of formula (Ie):

Embodiment 39

The compound of embodiment 1, wherein the compound is selected from agroup consisting of

wherein n is an integer having a value from 1-10.

Embodiment 40

The compound of embodiment 1, wherein the compound is selected from agroup consisting of

Embodiment 41

The compound of embodiment 1, wherein the compound is

Embodiment 42

The compound of embodiment 1, wherein the compound is

Embodiment 43

The compound of embodiment 1, wherein the compound is

Embodiment 44

The compound of embodiment 1, wherein the compound is

Embodiment 45

The compound of embodiment 1, wherein the compound is

Embodiment 46

The compound of embodiment 45, wherein the compound is

Embodiment 47

The compound of embodiment 1 wherein the compound is

Embodiment 48

The compound of embodiment 47, wherein the compound is

Embodiment 49

The compound of embodiment 11 wherein the compound is

Embodiment 50

The compound of embodiment 1, wherein the compound is

Embodiment 51

The compound of embodiment 1, wherein the compound is

Embodiment 52

The compound of embodiment 1, wherein the compound is

Embodiment 53

The compound of embodiment 1, wherein the compound is

Embodiment 54

The compound of embodiment 1, wherein the compound is

Embodiment 55

The compound of embodiment 1, wherein the compound is

Embodiment 56

The compound of embodiment 1, wherein the compound is

Embodiment 57

The compound of embodiment 1, wherein the compound is

Embodiment 58

The compound of embodiment 57, wherein the compound is

Embodiment 59

The compound of embodiment 1, wherein the compound is

Embodiment 60

The compound of embodiment 59, wherein the compound is

Embodiment 61

A compound of Formula II

wherein EDG is an electron donating group; Ar₂ and each Ar₁ isindependently C₁-C₁₄ arylene or C₁-C₁₄ heteroarylene, each optionallysubstituted with one more R₄₁; each R₄₁ is independently halogen, —OR₄₂,—CN, —NR₄₃R₄₄, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene whereinthe alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₄₅; R₄₂, R₄₃and R₄₄ are independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl,C₁-C₁₀ cycloalkyl, heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, each of which except for hydrogen is optionallysubstituted with one or more R₄₅; each R₄₅ is independently halogen,—OR₄₆, —NR₄₇R₄₈, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl,C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene; R₄₆,R₄₇ and R₄₈ are independently hydrogen or C₁-C₁₀ alkyl; EWG is anelectron withdrawing group; Y is absent, O, NH, or S; WSG is hydrogen ora water soluble group; x is an integer from 0-10; y is an integer from0-10; and z is an integer from 1-10.

Embodiment 62

The compound of embodiment 61, wherein EDG is OR₄₉, NR₅₀R₅₁, —SR₅₂,—PR₅₃R₅₄, —NR₅₅C(O)R₅₆, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₅₇; each R₅₇ is independently halogen, —OR₅₈,—NR₅₉R₆₀, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene; each of R₄₉,R₅₀, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₈, R₅₉ and R₆₀ is independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, each of whichexcept for hydrogen is optionally substituted with one or more R₆₁ andwherein R₅₀ and R₅₁ are optionally joined together to form aheterocycloalkyl or heteroaryl optionally substituted with R₆₁; each ofR₆₁ is independently halogen, —OR₆₂, —NR₆₃R₆₄, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₆₅; each of R₆₂, R₆₃ and R₆₄ is independently hydrogenor C₁-C₁₀ alkyl; and each R₆₅ is independently C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene.

Embodiment 63

The compound of any one of embodiments 61-62, wherein EDG is

Embodiment 64

The compound of any one of embodiments 61-63, wherein EDG is

Embodiment 65

The compound of any one of embodiments 61-64, wherein EWG is halogen,—CN, —NO₂, —SO₃H, —CR₆₆R₆₇R₆₈, COR₆₉, or COOR₇₀; each R₆₆, R₆₇ and R₆₈is independently hydrogen or halogen; R₆₉ is halogen, hydrogen, C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl,C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, arylene, or heteroarylene is optionallysubstituted with one or more R₇₁; R₇₀ is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₂; each R₇₁ and R₇₂ is independently C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀arylene, or C₁-C₁₀ heteroarylene.

Embodiment 66

The compound of one of embodiments 61-65, wherein EWG is selected from agroup consisting of F, Cl, Br, —CH═O, NO₂, —CF₃, —CCl₃, —SO₃ and —CN.

Embodiment 67

The compound of embodiment 66, wherein EWG is —CN.

Embodiment 68

The compound of any one of embodiments 61-67, wherein Y is absent.

Embodiment 69

The compound of any one of embodiments 61-68, wherein WSG is hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₇₃; each R₇₃is independently halogen, —OR₇₄, —NR₇₅R₇₆, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene, wherein the alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, arylene, or heteroarylene is optionally substitutedwith one or more R₇₇; each R₇₄, R₇₅ and R₇₆ is independently hydrogen,C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀heterocycloalkyl, C₁-C₁₀ arylene, or C₁-C₁₀ heteroarylene, wherein thealkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, arylene, orheteroarylene is optionally substituted with one or more R₇₇; each R₇₇is independently halogen, —OR₇₈, —NR₇₉R₈₀, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene; and each of R₇₈, R₇₉ and R₈₀ is independentlyhydrogen or C₁-C₁₀ alkyl.

Embodiment 70

The compound of any one of embodiments 61-69, wherein WSG is hydrogen.

Embodiment 71

The compound of any one of embodiments 61-69, wherein WSG is

Embodiment 72

The compound of embodiment 61-69, wherein WSG is polyethylene glycol,polypropylene glycol, co-polymer of polyethylene glycol andpolypropylene glycol, or alkoxy derivatives thereof.

Embodiment 73

The compound of embodiment 72, wherein WSG is

wherein n is an integer from 0-50 and R₈₁ is H, a C₁-C₁₀ alkyl, a C₁-C₁₀alkenyl, or a C₁-C₁₀ alkynyl wherein each wherein the alkyl, alkenyl, oralkynyl is optionally substituted with one or more C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, C₁-C₁₀ cycloalkyl, C₁-C₁₀ heterocycloalkyl, C₁-C₁₀ arylene,or C₁-C₁₀ heteroarylene.

Embodiment 74

The compound of any one of embodiments 72 or 73, wherein R₈₁ is methyl.

Embodiment 75

The compound of any one of embodiments 72 or 73, wherein R₈₁ isCH₂—C≡CH.

Embodiment 76

The compound of any one of embodiments 72-75, wherein n is 0, 1, 2, 3,4, 5, 6, 7, 8, 9, or 10.

Embodiment 77

The compound of any one of embodiments 72-76, wherein n is 3 or 6.

Embodiment 78

The compound of any one of embodiments 61-69, wherein the WSG is

Embodiment 79

The compound of embodiment 78, wherein the WSG is

Embodiment 80

The compound of any one of embodiments 61-69, wherein the WSG is

Embodiment 81

The compound of embodiment 80, wherein the WSG is

Embodiment 82

The compound of any one of embodiments 61-81, wherein each of Ar₁ isindependently a naphthylene or a phenylene.

Embodiment 83

The compound of embodiment 61-82, wherein Ar₂ is naphthylene, phenylene,or pyridyl.

Embodiment 84

The compound of embodiment 83, wherein Ar₂ is naphthylene or aphenylene.

Embodiment 85

The compound of embodiment 83, wherein Ar₂ is pyridyl.

Embodiment 86

The compound of embodiment 61, wherein the compound is selected from agroup consisting of

wherein n is an integer with value 0-10.

Embodiment 87

The compound of embodiment 61, wherein the compound is selected from agroup consisting of

Embodiment 88

The compound of embodiment 61, wherein the compound is

Embodiment 89

The compound of embodiment 61, wherein the compound is

Embodiment 90

The compound of embodiment 61, wherein the compound is

Embodiment 91

The compound of embodiment 61, wherein the compound is

Embodiment 92

A pharmaceutical composition comprising a compound according to any oneof embodiments 1-91.

Embodiment 93

The pharmaceutical composition of embodiment 92, further comprising oneor more pharmaceutically acceptable additive, carrier or excipientselected from a group consisting of ethanol, DMSO, polyethylene glycol,polypropylene glycol, aqueous acetate buffers, aqueous citrate buffers,aqueous phosphate buffers, aqueous carbonate buffers, cyclodextrins,corn oil, vitamin E, polysorbates, solutol and bile acids.

Embodiment 94

A composition comprising a compound according to any one of embodiments1-91 for use as a medicament.

Embodiment 95

The composition for use as a medicament of embodiment 92, furthercomprising one or more pharmaceutically acceptable additive, carrier orexcipient selected from a group consisting of ethanol, DMSO,polyethylene glycol, polypropylene glycol, aqueous acetate buffers,aqueous citrate buffers, aqueous phosphate buffers, aqueous carbonatebuffers, cyclodextrins, corn oil, vitamin E, polysorbates, solutol andbile acids

Embodiment 96

A composition comprising a compound according to any one of embodiments1-91 and an amyloid or amyloid like protein.

Embodiment 97

The composition of embodiment 96, wherein the amyloid or amyloid likeprotein is Aβ peptide, prion peptide, alpha-synuclein, or superoxidedismutase.

Embodiment 98

A method of detecting an amyloid or amyloid like protein comprising: a)contacting a compound according to any one of embodiments 1-91 with asample potentially comprising the amyloid or amyloid like protein,wherein in presence of an amyloid or amyloid like protein the compoundforms a detectable complex; and b) detecting the formation of thedetectable complex such that the presence or absence of the detectablecomplex correlates with the presence or absence of the amyloid oramyloid like protein.

Embodiment 99

The method of embodiment 98, wherein the detection of the formation ofthe detectable complex is performed by measuring a signal generated bythe detectable complex.

Embodiment 100

The method of embodiment 99, wherein the signal generated by thedetectable complex is an electromagnetic signal.

Embodiment 101

The method of embodiment 99, wherein the electromagnetic signal is afluorescence signal.

Embodiment 102

The method of embodiment 101, wherein the fluorescence signal ismeasures at a wavelength of 450-650 nm.

Embodiment 103

The method of embodiment 101, wherein the fluorescence signal ismeasures at a wavelength of 520-540 nm.

Embodiment 104

The method of embodiment 98, wherein the amyloid or amyloid like proteinis Aβ peptide, prion peptide, alpha-synuclein, or superoxide dismutase.

Embodiment 105

The method of embodiment 98, wherein the amyloid or amyloid like proteinis beta amyloid (1-42) (Aβ (1-42)).

Embodiment 106

The method of embodiment 98, wherein the detection of the formation ofthe detectable complex is performed within about 1 sec, about 5 sec,about 1 min, about 10 min, about 30 min or about 60 min of thecontacting of the compound according to any one of embodiments 1-91 withthe sample.

Embodiment 107

The method of embodiment 98, wherein the detection of the formation ofthe detectable complex is performed within about 1-5 minutes of thecontacting of the compound according to any one of embodiments 1-91 withthe sample.

Embodiment 108

A method of determining the presence or absence of one or more diseaseor condition in a subject comprising: a) administering to the subject aneffective amount of a compound according to any one of embodiments 1-91or a pharmaceutical composition thereof, wherein in presence of thedisease or condition the administered compound forms a detectablecomplex; and b) detecting the formation of the detectable complex suchthat presence or absence of detectable complex correlates with thepresence or absence of the disease or condition.

Embodiment 109

The method of embodiment 108, wherein the disease or condition ischaracterized by protein aggregation or protein misfolding.

Embodiment 110

The method of embodiment 108, wherein the disease or condition is anamyloid based disease or condition.

Embodiment 111

The method of embodiment 108, wherein the disease or condition isAlzheimer's disease (AD), Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), or Down'ssyndrome.

Embodiment 112

The method of embodiment 108, wherein the disease of condition isAlzheimer's disease.

Embodiment 113

The method of embodiment 112, wherein the compound is:

Embodiment 114

The method of embodiment 108, wherein the disease or condition is aprion disease or condition.

Embodiment 115

The method of embodiment 114, wherein the prion disease or condition isCreutzfeldt-Jakob disease (CJD).

Embodiment 116

The method of embodiment 108, wherein the administering is to the eye ofthe subject.

Embodiment 117

The method of embodiment 108, wherein the administering is parenteral.

Embodiment 118

The method of embodiment 108, wherein the administering is intravenous.

Embodiment 119

The method of embodiment 108, wherein the administering is subcutaneous.

Embodiment 120

The method of embodiment 108, wherein the administering isintramuscular.

Embodiment 121

The method of embodiment 108, wherein the administering is intrathecal.

Embodiment 122

The method of embodiment 108, wherein the administering is transmucosal.

Embodiment 123

The method of embodiment 108, wherein the administering is oral.

Embodiment 124

The method of embodiment 108, wherein the administering is buccal.

Embodiment 125

The method of embodiment 108, wherein the administering is sublingual.

Embodiment 126

The method of embodiment 108, wherein the administering is nasal.

Embodiment 127

The method of embodiment 108, wherein the administering is pulmonary.

Embodiment 128

The method of embodiment 108, wherein the administering is rectal.

Embodiment 129

The method of embodiment 108, wherein the administering is topical.

Embodiment 130

The method of embodiment 108, wherein the administering is ocular.

Embodiment 131

The method of embodiment 108, wherein the administering is transdermal.

Embodiment 132

The method of embodiment 108, wherein the administering is intradermal.

Embodiment 133

The method of embodiment 108, wherein the administering is systemic.

Embodiment 134

The method of embodiment 108, wherein the detection of the formation ofthe detectable is performed within about 1 sec, about 5 sec, about 1min, about 10 min, about 30 min or about 60 min of the administration ofthe compound according to any one of embodiments 1-91 to the subject.

Embodiment 135

The method of embodiment 108, wherein the detection of the formation ofthe detectable complex is performed within about 1-5 min of theadministration of the compound according to any one of embodiments 1-91to the subject.

Embodiment 136

The method of embodiment 108, wherein the effective amount the compoundcorresponds to about 50-500 mg of compound per adult human subject.

Embodiment 137

The method of embodiment 108, wherein the detection of the formation ofthe detectable complex is performed by measuring a signal generated bythe detectable complex.

Embodiment 138

The method of embodiment 137, the signal generated by the detectablecomplex is an electromagnetic signal.

Embodiment 139

The method of embodiment 138, wherein the electromagnetic signal is afluorescence signal.

Embodiment 140

The method of embodiment 139, wherein the fluorescence signal ismeasures at a wavelength of 450-650 nm.

Embodiment 141

The method of embodiment 139, wherein the fluorescence signal ismeasures at a wavelength of 520-540 nm.

Embodiment 142

Use of a composition containing a therapeutically effective amount of acompound according to any one of embodiments 1-91 for treating,ameliorating the symptoms of or preventing at least one disease orcondition.

Embodiment 143

The use of embodiment 142, wherein the disease or condition ischaracterized by protein aggregation or protein misfolding,

Embodiment 144

The use of any one of embodiments 142 or 143, wherein the disease orcondition is an amyloid based disease or condition.

Embodiment 145

The use of any one of embodiments 142=144, wherein the disease orcondition is Alzheimer's disease (AD), Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD),or Down's syndrome.

Embodiment 146

The use of embodiment 145, wherein the disease is Alzheimer's disease.

Embodiment 147

The use of any one of embodiments 142-146, wherein the compound is:

Embodiment 148

The use of embodiment 142, wherein the disease or condition is a priondisease or condition.

Embodiment 149

The use of embodiment 148, wherein the prion disease or condition isCreutzfeldt-Jakob disease.

Embodiment 150

The use of any one of embodiments 142-149, wherein the therapeuticallyeffective amount corresponds to about 50-500 mg.

Embodiment 151

A screening method comprising administering to a subject an effectiveamount of a compound according to any one of embodiments 1-91 or apharmaceutical composition thereof, wherein upon administration of acompound according to any one of embodiments 1-91 form a detectablecomplex.

Embodiment 152

The screening method of embodiment 151, further comprising measuring asignal generated by the by the detectable complex or by the compound,according to any one of embodiments 1-91, administered to the subject.

Embodiment 153

The screening method of embodiment 152, further comprising making aclinical decision based on the measured signal.

Embodiment 154

The screening method of embodiment 152, wherein the signal is anelectromagnetic signal.

Embodiment 155

The screening method of embodiment 154, wherein the electromagneticsignal is a fluorescence signal.

Embodiment 156

The method of embodiment 155, wherein the fluorescence signal ismeasures at a wavelength of 450-650 nm.

Embodiment 157

The method of embodiment 155, wherein the fluorescence signal ismeasures at a wavelength of 520-540 nm.

Embodiment 158

The screening method of embodiment 151, wherein the administering is tothe eye of the subject.

Embodiment 159

The screening method of embodiment 151, wherein the administering isparenteral.

Embodiment 160

The screening method of embodiment 151, wherein the administering isintraveinous.

Embodiment 161

The screening method of embodiment 151, wherein the administering issubcutaneous.

Embodiment 162

The screening method of embodiment 151, wherein the administering isintramuscular.

Embodiment 163

The screening method of embodiment 151, wherein the administering isintrathecal.

Embodiment 164

The screening method of embodiment 151, wherein the administering istransmucosal.

Embodiment 165

The screening method of embodiment 151, wherein the administering isoral.

Embodiment 166

The screening method of embodiment 151, wherein the administering isbuccal.

Embodiment 167

The screening method of embodiment 151, wherein the administering issublingual.

Embodiment 168

The screening method of embodiment 151, wherein the administering isnasal.

Embodiment 169

The screening method of embodiment 151, wherein the administering ispulmonary.

Embodiment 170

The screening method of embodiment 151, wherein the administering isrectal.

Embodiment 171

The screening method of embodiment 151, wherein the administering istopical.

Embodiment 172

The screening method of embodiment 151, wherein the administering isocular.

Embodiment 173

The screening method of embodiment 151, wherein the administering istransdermal.

Embodiment 174

The screening method of embodiment 151, wherein the administering isintradermal.

Embodiment 175

The screening method of embodiment 151, wherein the said administeringis systemic.

Embodiment 176

A kit for comprising a compound according to any one of embodiments1-91.

Embodiment 177

The kit of embodiment 176 further comprising instructions for a) usingthe compound for the binding to an amyloid or amyloid like protein toform a detectable complex; and b) detecting the formation of thedetectable complex such that presence or absence of detectable complexcorrelates with the presence or absence of the amyloid or amyloid likeprotein.

Embodiment 178

The kit of embodiment 176 further comprising instructions for a) usingthe compound for binding to an amyloid or amyloid like protein to form adetectable complex; and b) detecting changes in abundance of thedetectable complex over time such that the changes in the abundance ofthe detectable complex over time are correlated to changes in abundanceof amyloid or amyloid like protein over time.

Embodiment 179

The kit of embodiment 178, further comprising instructions forcorrelating the changes in the abundance of the detectable complex tomonitor progression of a disease.

Embodiment 180

The kit of embodiment 176, wherein the compound according to any one ofembodiments 1-91 is contained in a container as a sterile liquidformulation.

Embodiment 181

The kit of embodiment 176, wherein the compound according to any one ofembodiments 1-91 is contained in a container as a sterile freeze-driedformulation.

Embodiment 182

The kit of embodiment 176, wherein the container is an amber vial.

Embodiment 183

The kit of embodiment 176, wherein the container is capable ofprotecting light sensitive compounds or formulation.

EXAMPLES

The following examples are intended to illustrate but not limit thedisclosed embodiments.

Example 1:(E)-2-Cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide(Compound 1). See FIG. 1A for Synthetic Scheme

Step 1: Preparation of 2-(2-(2-methoxyethoxy)ethoxy)ethyl4-methylbenzenesulfonate (A1)

To a solution of dry pyridine (49 mL) in dichloromethane (DCM) (152 mL)was added commercially available triethylene glycol monomethyl ether(TEGMe) (20 g, 0.122 mol). The solution was cooled to 0° C., upon whichpara-toluenesulfonyl chloride (27.9 g, 0.146 mol) was added in oneportion with stirring. The reaction was let stir to room temperature(r.t.) over 24 hours, upon which the reaction as concentrated underreduced pressure. The resulting yellow oil was resuspended with ethylacetate (EtOAc), filtered, and concentrated to dry. The oil was purifiedby silica gel chromatography (2:8 EtOAc:hexanes) to obtain2-(2-(2-methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate A1 as aclear oil in 53% yield.

Step 2: Preparation of 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (A2)

To a solution of 2-(2-(2-methoxyethoxy)ethoxy)ethyl4-methylbenzenesulfonate (A1, 1.0 g, 3.14 mmol) in dry dimethylformamide(DMF) (125 mL) was added sodium azide (510 mg, 7.85 mmol) in one portionwith stir. The solution was flushed with argon and refluxed at 67° C.for 12 hours, upon which the reaction was cooled to r.t., diluted withice-cold water (125 mL) and extracted with diethyl ether (Et₂O). Theorganic washes were combined, washed with water and brine, dried overmagnesium sulfate, and concentrated to partial dryness in vacuo toobtain the azido-TEGMe as a clear oil.

The azide (3.0 g, 15.7 mmol) was dissolved in Et₂O (630 mL) and cooledto 0° C. with stir. To the reaction was added triphenyl phosphine (5.0g, 18.8 mmol) in one portion and the resulting solution let stir to r.t.over 24 hours, upon which water (200 mL) was then added and stirred foran additional 12 hours. Finally, toluene (150 mL) was added and theaqueous layer extracted, washed with toluene, and concentrated underreduced pressure to obtain 2-(2-(2-methoxyethoxy)ethoxy)ethanamine A2 asa yellow oil in 70% yield.

Step 3: Preparation of2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)acetamide (A3)

A solution of cyanoacetic acid (621 mg, 7.3 mmol) in anhydrous DCM (15mL) was cooled to 0° C. Separately, a solution of hydroxybenzothiazole(HOBt) (1.48 g, 10.97 mmol) and 2-(2-(2-methoxyethoxy)ethoxy)ethanamine(A2, 1.79 g, 10.97 mmol) was prepared in DCM (10 mL); this solution wasthen added dropwise to the cooled solution of cyanoacetic acid. Theresulting solution was allowed to stir for 10 minutes at 0° C., uponwhich 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (2.1 g, 10.97mmol) was added in one portion and the reaction stirred under argon at0° C. for 12 hours. The reaction was then concentrated and purified bysilica gel chromatography (0-2% MeOH/DCM) to obtain2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)acetamide A3 as a yellowoil in 83% yield.

Step 4: Preparation of 6-bromo-2-naphthaldehyde (A5)

A solution of commercially available methyl 6-bromo-2-naphthoate (A4,3.5 g, 13.2 mmol) in anhydrous tetrahydrofuran (THF) (70 mL) was cooledto 0° C. under nitrogen, upon which a solution of diisobutylaluminumhydride (DIBAL-H) in THF (15.8 mmol) was added dropwise over 5 minuteswith stir. The reaction was let stir to r.t. overnight, upon which itwas quenched with MeOH (50 mL) and a saturated sodium potassium tartratesolution (50 mL). The solution was then extracted with EtOAc and theorganic layers washed with water and brine, dried over sodium sulfate,and concentrated to obtain the corresponding alcohol as a white solid.

The alcohol (1.3 g, 5.48 mmol) was then dissolved in anhydrous DCM (28mL) under nitrogen with stir. To this solution was added pyridiniumchlorochromate (PCC) (1.4 g, 6.58 mmol) in one portion and the resultingbrown solution refluxed at 60° C. under nitrogen. After 6 hours, theresulting black solution was cooled to r.t. and poured into ice-coldEt₂O, filtered through ecliptic over a pad of silica, concentrated to ayellow solid, and finally purified with silica gel chromatography (8:2hexanes:EtOAc) to obtain the 6-bromo-2-naphthaldehyde A5 as a whitesolid in 95% yield.

Step 5: Preparation of 6-(piperidin-1-yl)-2-naphthaldehyde (A6)

6-Bromo-2-naphthaldehyde (A5, 1.5 g, 6.38 mmol), palladium (II) acetate(0.17 g, 0.64 mmol), and cesium carbonate (3.2 g, 9.57 mmol) were addedto dry, degassed toluene (16 mL) under argon and let stir for 30 minutesat r.t., upon which tri-t-butyl phosphine (2.55 mmol) was added dropwiseand the orange solution let stir an additional 10 minutes. Piperidine(0.75 mL, 7.66 mmol) was then added dropwise and the reaction refluxedat 110° C. for three days. The reaction was then cooled, diluted withDCM, filtered, and concentrated under reduced pressure to obtain a redoil which was purified by silica gel chromatography (0-1% MeOH/DCM) toobtain the 6-(piperidin-1-yl)-2-naphthaldehyde A6 as a yellow solid in70% yield.

Step 6: Preparation of(E)-2-Cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide(Compound 1)

6-(Piperidin-1-yl)-2-naphthaldehyde (A6, 150 mg, 0.627 mmol) and2-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)acetamide (115 mg, 0.501mmol) were dissolved in anhydrous THF (2.5 mL). To this reaction wasadded piperidine (0.013 mmol) and the reaction heated to 50° C.; achange in reaction color of yellow to orange was observed. After 12hours of heating, the reaction was cooled, concentrated to an oil, andpurified by silica gel chromatography (0-20% acetone/toluene) to obtain(E)-2-Cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamideas a yellow solid in 61% yield. R_(f)=0.25 (5% acetone/toluene); ¹H NMR(500 MHz, CDCl₃) δ 8.33 (s, 1H), 8.11 (s, 1H), 8.00-8.02 (dd, J=8.5 Hz,1.5 Hz, 1H), 7.69-7.71 (d, J=9.5 Hz, 1H), 7.60-7.62 (d, J=8.5 Hz, 1H),7.24-7.26 (m, 1H), 7.01 (bs, 1H), 6.84 (m, 1H), 3.64-3.66 (m, 6H),3.62-3.63 (m, 4H), 3.54-3.55 (m, 2H), 3.35 (s, 3H), 3.12-3.34 (m, 4H),1.69 (m, 4H), 1.61-1.62 (m, 2H); ¹³C (125 MHz, CDCl₃) δ 161.2, 152.9,151.6, 137.2, 133.8, 130.3, 127.2, 126.6, 126.1, 125.7, 119.4, 117.8,108.6, 100.5, 71.9, 70.6, 70.6, 70.5, 69.4, 59.0, 49.5, 40.2, 25.5,24.3; HRMS calcd for C₂₆H₃₂N₂O₅Na [M+Na]⁺474.2363, found 474.2363 byESI.

Example 2:(E)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide(Compound 2). See FIG. 3 for Synthetic Scheme

Step 1: Preparation of cyanomethanesulfonyl chloride (B4)

Chloroacetonitrile (B3, 5.0 g, 41.68 mmol) was added to a suspension ofsodium sulfite (5.3 g, 41.68 mmol) in water (25 mL). The mixture wasstirred at r.t. for 1 hour, upon which the water was removed underreduced pressure, and the resulting solid recrystallized from 98%ethanol (EtOH). The crude recrystallized product (3.0 g, 20.97 mmol) wassuspended in phosphoryl chloride (7.35 mL) and powdered phosphorouspentachloride (4.4 g, 20.97 mmol) and the solution stirred for 3 hoursat 70° C. under argon with exclusion of moisture. The reaction was thenfiltered and excess phosphoryl chloride removed by reduced pressure; thecrude oil was then distilled and cyanomethanesulfonyl chloride B4isolated as a clear-yellow oil in 13% yield.

Step 2: Preparation of1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)methanesulfonamide (B5)

Cyanomethanesulfonyl chloride was found to be relatively unstable in airand was reacted immediately (3.44 mmol) with previously synthesized2-(2-(2-methoxyethoxy)ethoxy)ethanamine (A2, 5.41 mmol) in DCM (10 mL).HOBt (5.43 mmol) was added dropwise to the reaction mixture once cooledto 0° C., followed by EDC (5.43 mmol). The reaction was then let stirfor 6 hours at 0° C., concentrated under reduced pressure, and purifiedby silica gel chromatography to obtain the1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)methanesulfonamide B5 in86% yield as a clear oil.

Step 3: Preparation of(E)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamide(Compound 2)

6-(Piperidin-1-yl)-2-naphthaldehyde (A6, 22.4 mg, 0.094 mmol) and1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)methanesulfonamide (B5,20.0 mg, 0.075 mmol) were dissolved in anhydrous THF (0.38 mL). To thisreaction was added piperidine (0.009 mmol) and the reaction heated to50° C. After 5 hours of heating, the reaction was cooled, concentratedto an oil, and purified by silica gel chromatography (0-20%Et₂O/hexanes) to obtain(E)-1-cyano-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2-(6-(piperidin-1-yl)naphthalen-2-yl)ethenesulfonamideas an orange oil in 73% yield. R_(f)=0.5 (100% diethyl ether); ¹H NMR(500 MHz, CDCl₃) d 8.12 (s, 1H), 8.05 (s, 1H), 7.98-8.00 (dd, J=9.0 Hz,2.0 Hz, 1H), 7.74-7.76 (d, J=9.5 Hz, 1H), 7.64-7.66 (d, J=9.0 Hz, 1H),7.29-7.31 (dd, J=9.0 Hz, 2.5 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 5.48 (bs,1H), 3.64-3.68 (m, 8H), 3.53-3.57 (m, 3H), 3.39-3.42 (m, 3H), 3.38 (s,3H), 3.33-3.35 109 (m, 2H), 1.73 (m, 4H), 1.67 (m, 2H); ¹³C NMR (125MHz, CDCl₃) δ 161.2, 152.9, 151.6, 137.2, 133.8, 130.3, 127.2, 126.6,126.1, 125.7, 119.4, 117.8, 108.6, 100.5, 71.9, 70.6, 70.6, 70.5, 69.4,59.0, 49.5, 40.2, 25.5, 24.3; HRMS calcd. for C₂₅H₃₃N₃O₅SNa [M+Na]+510.2033, found 510.2035 by ESI.

Example 3:(E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide(Compound 3). See FIG. 5 for Synthetic Scheme

Step 1: Preparation of 2,5,8,11,14,17-hexaoxanonadecan-19-ol

2-(2-(2-Methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (A1, 1.0 g,3.14 mmol) was added with stir to triethylene glycol (2.10 mL, 15.7mmol). Potassium hydroxide (510 mg, 9.42 mmol) was ground into a powderand added to the reaction and the mixture refluxed at 100° C. for 12hours, upon which the reaction was diluted with water (50 mL) andextracted with DCM. The organic layers were combined, dried over sodiumsulfate, and concentrated under reduced pressure to obtain2,5,8,11,14,17-hexaoxanonadecan-19-ol as a yellow oil in 69% yield.

Step 2: Preparation of 2,5,8,11,14,17-hexaoxanonadecan-19-yl4-methylbenzenesulfonate (C2)

2,5,8,11,14,17-Hexaoxanonadecan-19-ol (4.0 g, 13.5 mmol) was dissolvedin DCM (55 mL) with stir. Triethylamine (2.82 mL, 20.2 mmol) was thenadded and the resulting mixture cooled to 0° C., upon whichpara-toluenesulfonyl chloride (3.86 g, 20.2 mmol) was added in oneportion. The reaction mixture was then stirred to r.t. for 24 hours, andthen concentrated under reduced pressure to obtain an oil. The oil wasresuspended in EtOAc, filtered, concentrated, and purified by silica gelchromatography (80% EtOAc/hexanes to 5% MeOH/EtOAc) to yield2,5,8,11,14,17-hexaoxanonadecan-19-yl 4-methylbenzenesulfonate C2 as ayellow oil in 77% yield.

Step 3: Preparation of 2,5,8,11,14,17-hexaoxanonadecan-19-amine (C3)

To a solution of 2,5,8,11,14,17-hexaoxanonadecan-19-yl4-methylbenzenesulfonate (C2, 1.0 g, 3.37 mmol) in dry DMF (55 mL) wasadded sodium azide (360 mg, 5.54 mmol) in one portion with stir. Thesolution was flushed with argon and refluxed at 70° C. for 12 hours,upon which the reaction was cooled to r.t., diluted with ice-cold water(50 mL) and extracted with Et₂O. The organic washes were combined,washed with water and brine, dried over magnesium sulfate, andconcentrated in vacuo to obtain the azido-hexaethylene glycol monomethylether as a clear oil in 91% yield.

Azido-hexaethylene glycol monomethyl ether (130 mg, 0.44 mmol) wasdissolved in anhydrous ethanol and 15% activated palladium on carbon(Pd/C) was added. The reaction mixture was subjected to a high-pressurehydrogenation for 4 hours at 50-60 PSI. Upon completion, the reactionmixture was filtered with MeOH and the solution was concentrated underreduced pressure to obtain 2,5,8,11,14,17-hexaoxanonadecan-19-amine C3as a clear oil in 45% yield over the two steps.

Step 4: Preparation of2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)acetamide (C4)

To a solution of 2,5,8,11,14,17-hexaoxanonadecan-19-amine (C3, 50 mg,0.169 mmol) and cyanoacetic acid (9.6 mg, 0.588 mmol) in DCM (0.45 mL)cooled to 0° C. was added HOBt (38.8 mg, 0.254 mmol) dropwise as asolution in DCM (0.40 mL). EDC (40 mg, 0.254 mmol) was then added in oneportion and the reaction let stir at 0° C. for 12 hours, upon which itwas concentrated under reduced pressure and purified via silica gelchromatography (1:1 EtOAc:hexanes to 10% MeOH/EtOAc) to obtain2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)acetamide C₄ as a clearoil in 80% yield.

Step 5: Preparation of(E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide(Compound 3)

6-(Piperidin-1-yl)-2-naphthaldehyde (A6, 12 mg, 0.050 mmol) and2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)acetamide (C4, 15 mg,0.041 mmol) were dissolved in anhydrous THF (0.25 mL). To this reactionwas added piperidine (0.005 mmol) and the reaction heated to 50° C.After 12 hours of heating, the reaction was cooled, concentrated to anoil, and purified by silica gel chromatography (3% MeOH/EtOAc) to obtain(E)-2-cyano-N-(2,5,8,11,14,17-hexaoxanonadecan-19-yl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamideas an orange oil in 62% yield. R_(f)=0.35 (3% MeOH/EtOAc); ₁H NMR (500MHz, δ, ppm, CDCl₃): 1.68 (m, 6H); 3.30 (s, 3H); 3.33 (m, 3H); 3.46 (t,2H); 3.53-3.62 (m, 20H); 6.83 (bs, 1H); 6.99 (d, 2H); 7.22-7.24 (dd,1H); 7.59 (d, 1H); 7.69 (d, 1H), 7.98 (dd, 1H), 8.10 (s, 1H). ¹³C NMR(125 MHz, δ, ppm, CDCl₃): 136.4, 132.9, 129.5, 126.4, 125.8, 125.2,124.9, 118.6, 116.9, 107.8, 99.7, 71.0, 69.7, 69.6, 69.5, 68.6, 58.1,51.9, 48.7, 39.3, 28.8, 24.7, 23.5, 7.2; HRMS: calcd. for C₃₂H₄₅N₃O₇:[M+Na]⁺606.3150, found 606.3151 by ESI.

Example 4:(E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide.Sec FIG. 7 for a Synthetic Scheme

Step 1: Preparation of 2-cyano-N-(2,3-dihydroxypropyl)acetamide (D3)

To a solution of 3-amino-1,2-propanediol (D2, 455 mg, 5.0 mmol) wasadded methyl cyanoacetate (D1, 457 mg, 4.6 mmol) with stir. The mixturewas let stir overnight at r.t., upon which the reaction was purified bysilica gel chromatography (10% MeOH/EtOAc) to yield2-cyano-N-(2,3-dihydroxypropyl)acetamide D3 as a white solid in 65%yield.

Step 2: Preparation of2-cyano-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)acetamide (D4)

2-Cyano-N-(2,3-dihydroxypropyl)acetamide (D3, 120 mg, 0.76 mmol) wasdissolved in acetone (3 mL) and para-toluenesulfonic acid (80 mg, 0.42mmol) was added. The resulting mixture was refluxed for 12 hours, uponwhich the crude reaction was purified by silica gel chromatography (2.5%MeOH/DCM) to yield2-cyano-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)acetamide D4 as awhite solid in 53% yield.

Step 3: Preparation of(E)-2-cyano-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide(D8)

6-(Piperidin-1-yl)-2-naphthaldehyde (A6, 12 mg, 0.05 mmol) and2-cyano-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)acetamide (D4, 13 mg,0.066 mmol) in anhydrous THF (1.5 mL) was added piperidine (0.005 mmol)and the resulting mixture refluxed for 12 hours. The reaction was thenconcentrated under reduced pressure to an oil, which was purified viasilica gel chromatography (5% MeOH/DCM) to obtain(E)-2-cyano-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamideD8 as a red solid in 72% yield.

Step 4: Preparation of(E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide(Compound 5)

(E)-2-cyano-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamide(D8, 5 mg, 0.012 mmol) was hydrolyzed with 1 N hydrochloric acid (HCl)in MeOH (3 mL) via reflux for 12 hours. The reaction was thenconcentrated under reduced pressure and the crude residue dissolved in amixture of 1:2 MeOH:dimethylsulfoxide (DMSO). The solution was thenpurified by preparative reverse-phase high-performance liquidchromatography (RP-HPLC) (grad. 5-90% acetonitrile in water, 20 min.) toafford(E)-2-cyano-N-(2,3-dihydroxypropyl)-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamideas a red solid in 33% yield. ¹H NMR (300 MHz, CD₃OD) δ 8.47 (s, 1H),8.37 (s, 1H), 8.19 (dd, J=1.9, 1.8 Hz, 1H), 7.91 (d, J=9.1 Hz, 1H), 7.83(d, J=8.6 Hz, 1H), 7.50 (dd, J=2.3, 2.2 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H),4.38 (d, J=5.3 Hz, 2H), 4.21-4.15 (m, 2H), 3.89-3.83 (m, 1H), 3.58-3.50(m, 4H), 1.82-1.75 (m, 6H). HRMS (EST-TOF-MS): m/z calc. for C₂₂H₂₆N₃O₃⁻: 380.1969; found: 380.1988.

Example 5:242-(2-(2-methoxyethoxy)ethoxy)ethoxy)-4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile(Compound 17). See FIG. 9 for a Synthetic Scheme

Step 1: Preparation of 6-(piperidin-1-yl)-naphthalen-2-yltrifluoromethanesulfonate (G2)

6-Bromonaphthalen-2-yl trifluoromethanesulfonate G1 (500 mg, 1.41 mmol),palladium (II) acetate (16 mg, 0.05 mmol), and sodium tert-butoxide (176mg, 1.83 mmol) were dissolved in degassed toluene (13 mL) under argonand let stir for 30 minutes at r.t., upon which tri-t-butyl phosphine(0.1 mmol) was added dropwise and the solution let stir an additional 10minutes. Piperidine (0.17 mL, 1.69 mmol) was then added dropwise and thereaction refluxed at 110° C. for three days. The reaction was thencooled, diluted with DCM, filtered through celite, and concentratedunder reduced pressure to obtain a red oil which was purified by silicagel chromatography (0-8% EtOAc/hexanes) to obtain6-(piperidin-1-yl)-naphthalen-2-yl trifluoromethanesulfonate G2 as awhite solid in 61% yield.

Step 2: Preparation of2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(G4)

2,2,6,6-Tetramethyl-piperidine (TMP) (1.07 g, 7.58 mmol) was dissolvedin anhydrous THF (14 mL) and cooled to −78° C. under argon, upon whichn-butyllithium (n-BuLi) (7.22 mmo) was added dropwise over 15 minuteswith stir. A solution of 2-chloronicotinonitrile G3 (500 mg, 3.609 mmol)in anhydrous THF (7.3 mL) was then added dropwise with stir over 15minutes. Finally, a solution of triisopropyl borate (1.43 g, 7.58 mmol)in anhydrous THF (3.6 mL) was added dropwise over 15 minutes. Thereaction was let stir for 30 minutes, which was then warmed to r.t. andquenched with water (50 mL) and slightly acidified with hydrochloricacid (HCl). The mixture was then extracted with EtOAc and the organiclayers dried and concentrated to obtain the boronic acid.

The boronic acid (26 mg, 0.143 mmol), pinnacol (17 mg, 0.143 mmol), andmagnesium sulfate (100 mg, 0.83 mmol) were dissolved in anhydroustoluene (1 mL) and the reaction let stir for 12 hours, upon which it wasfiltered and the resulting solution washed with brine and concentratedunder reduced pressure to obtain2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrileG4 in 17% yield.

Step 3: Preparation of2-chloro-4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile (G5)

2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrileG4 (25 mg, 0.094 mmol), 6-(piperidin-1-yl)-naphthalen-2-yltrifluoromethanesulfonate G2 (17 mg, 0.047 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)) (3.4 mg, 0.005 mmol), copper(I) chloride (5 mg, 0.05mmol), and cesium carbonate (31 mg, 0.094 mmol) were dissolved inanhydrous DMF (0.5 mL) and heated to 90° C. for 3 hours at standardpressure. The reaction was then diluted with DCM and water, andextracted with DCM. The organic layers were washed with water and brine,dried, and concentrated under reduced pressure to obtain a crude oilwhich was purified by silica gel chromatography (0-10% EtOAc/hexanes) toobtain 2-chloro-4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile G5in 71% yield.

Step 4: Preparation of2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile(Compound 17)

Triethylene glycol monomethyl ether (TEGMe) (25 mg, 0.14 mmol) wasstirred with anhydrous DMF (0.025 mL) was cooled to 0° C. and sodiumhydride (1 mg, 0.04 mmol) added. A solution of2-chloro-4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile G5 (5 mg,0.014 mmol) in anhydrous DMF (0.04 mL) was then added slowly. Thereaction was headed to 60° C. for 12 hours, upon which it was removedand concentrated under reduced pressure. The residue was then purifiedby preparative thin-layer chromatography (0-5% MeOH/EtOAc) to obtain24242-(2-methoxyethoxy)ethoxy)ethoxy)-4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrileas a dark-yellow oil in 70% yield. R_(f)=0.40 (5% MeOH/EtOAc); ¹H NMR(500 MHz, CDCl₃) δ 8.29-8.30 (d, J=1H), 7.98 (s, 1H), 7.77 (s, 2H), 7.61(s, 1H), 7.33-7.34 (d, J=Hz, 1H), 7.11-7.12 (d, 2H), 4.63-4.65 (t, 2H),3.93-3.95 (m, 2H), 3.66-3.70 (m, 4H), 3.54-3.56 (m, 2H), 3.37 (s, 3H),3.32 (bs, 4H), 1.76 (bs, 4H), 1.64 (bs, 2H); ¹³C (125 MHz, CDCl₃) δ165.16, 155.89, 150.38, 132.71, 129.03, 128.80, 128.51, 128.29, 126.52,125.23, 123.67, 121.34, 117.61, 115.19, 109.43, 95.41, 72.03, 71.13,7084, 70.70, 69.29, 67.14, 59.20, 53.07, 32.08, 29.83; HRMS calcd forC₂₈H₃₃N₃O₄Na [M+Na]⁺498.2361, found 498.2363 by ESI.

Example 6: 4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile(Compound 18). See FIG. 11 for a Synthetic Scheme

Step 1: Preparation of 6-(piperidin-1-yl)naphthalen-2-ol (H2)

6-Bromonaphthalen-2-ol (100 mg, 0.45 mmol), palladium (II) acetate (11.2mg, 0.05 mmol), and cesium carbonate (234 mg, 0.72 mmol) were added todry, degassed toluene (3 mL) under argon and let stir for 30 minutes atr.t., upon which tri-t-butyl phosphine (0.2 mmol) was added dropwise andthe solution let stir an additional 10 minutes. Piperidine (0.123 mL,1.34 mmol) was then added dropwise and the reaction refluxed at 110° C.for three days. The reaction was then cooled, diluted with DCM,filtered, and concentrated under reduced pressure to obtain a red oilwhich was purified by silica gel chromatography (10% DCM/hexanes) toobtain the 6-(piperidin-1-yl)-naphthalen-2-ol H2 as a white solid in 33%yield.

Step 2: Preparation of 6-(piperidin-1-yl)-naphthalen-2-yltrifluoromethanesulfonate (H3)

6-(Piperidin-1-yl)-naphthalen-2-ol (H2, 23 mg, 0.01 mmol) was dissolvedin DCM (2 mL) and pyridine (0.05 mL) was added and the reaction cooledto 0° C. Trifluoromethanesulfonic anhydride (Tf₂O) (33.8 mg, 0.12 mmol)was then added dropwise and the resulting mixture stirred at r.t. for 1hour, upon which it was concentrated under reduced pressure and thecrude purified by silica gel chromatography (5% MeOH/DCM) to obtain6-(piperidin-1-yl)-naphthalen-2-yl trifluoromethanesulfonate H3 as awhite solid in 44% yield.

Step 3: Preparation of4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile (Compound 18)

6-(Piperidin-1-yl)-naphthalen-2-yl trifluoromethanesulfonate (1-13, 13.5mg, 0.038 mmol), 3-cyanopyridine-4-boronic acid pinacol ester (fromExample A5, Step 2, 24 mg, 0.11 mmol),tetrakis(triphenylphosphine)palladium(0) (25.4 mg, 0.022 mmol), andcesium carbonate (40 mg, 0.12 mmol) were added to degassed anhydrous THF(6 mL) and the reaction refluxed for 12 hours. The mixture was thencooled to r.t., diluted with DCM, filtered, and concentrated underreduced pressure to ontain the crude oil, which was then purified bysilica gel chromatography (4% acetone/DCM) to afford4-(6-(piperidin-1-yl)naphthalen-2-yl)nicotinonitrile as a yellow solidin 46% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.80 (s, 1H), 8.02(s, 1H), 7.82 (s, 2H), 7.60 (dd, J=24.4, 6.6 Hz, 2H), 7.37 (s, 1H), 7.14(s, 1H), 3.35 (s, 4H), 1.78 (s, 4H), 1.66 (s, 2H). MS (ESI): m/z calc.for C₂₁H₁₉N₃ ⁺: 313.16; found: 314.41. [M+H]⁺. HRMS (ESI-TOF-MS): m/zcalc. for C₂₁H₂₀N₃ ⁺: 314.1652; found: 314.1664.

Example 7:(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide.See FIG. 14 for a Synthetic Scheme

Step 1: Preparation of 2-(2-(2-azidoethoxy)ethoxy)ethanol (E1)

2-[2-(2-Chloroethoxy)ethoxy]ethanol (300 mg, 1.8 mmol), NaN₃ (350 mg,5.4 mmol) and TBAI (66.2 mg, 0.18 mmol) were added to DMF (4 mL). Themixture was heated to 70° C. and stirred under N₂ overnight. Solvent wasremoved under reduced pressure and the product was purified via columnchromatography (EtOAc:hexane=1:1) to afford2-(2-(2-azidoethoxy)ethoxy)ethanol E1 (268 mg, 85%)

Step 2: Preparation of 3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)prop-1-yne(E2)

2-(2-(2-Azidoethoxy)ethoxy)ethanol (E1, 140 mg, 0.8 mmol), propargylbromide (190 mg, 1.6 mmol) and NaH (23 mg, 0.095 mmol) were added to DMF(2 mL). The mixture was stirred at room temperature overnight. Solventwas removed under reduced pressure and the product was purified viacolumn chromatography (EtOAc:hexane=1:4) to afford3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)prop-1-yne E2 (106 mg, 62%).

Step 3: Preparation of 2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethanamine(E3)

3-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)prop-1-yne (E2, 30 mg, 0.14 mmol)and Ph₃P (55 mg, 0.21 mmol) were added to THF (2 mL). The mixture wasstirred at room temperature for 2 h. H₂O (1 mL) was added and thereaction was stirred at room temperature overnight. Solvent was removedunder reduced pressure and the product was purified via columnchromatography (CH₂Cl₂:MeOH:TEA=100:2:1) to afford2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethanamine E3 (13 mg, 50%).

Step 4: Preparation of2-cyano-N-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethyl)acetamide (E4)

A mixture of cyanoacetic acid (10 mg, 0.1 mmol),2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethanamine (E3, 30 mg, 0.16 mmol),EDC (30 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol) and CH₂Cl₂ (2 mL) wasstirred and cooled to 0° C. The mixture was allowed to warm up to roomtemperature and stirred for 5 h. The solution was concentrated underreduced pressure and the product was purified via column chromatography(EtOAc:MeOH=50:1) to afford2-cyano-N-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethyl)acetamide E4 (22mg, 88%).

Step 5: Preparation of(3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl4-methylbenzenesulfonate (E5)

Methyl α-D-glucopyranoside (0.3 g, 1.56 mmol) was dissolved in pyridine(3 mL) and cooled to 0° C. under argon. p-Toluenesulfonyl chloride (0.3g, 1.56 mmol) was added and the solution was stirred overnight. Themixture was then concentrated under reduced pressure and purified viacolumn chromatography (EtOAc) to afford(3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl4-methylbenzenesulfonate E5 (0.28 g, 52%).

Step 6: Preparation of2-methoxy-6-(tosyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate(E6)

To a solution of(3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl4-methylbenzenesulfonate (E5, 0.6 g, 1.72 mmol) in dry pyridine (4 mL)was added acetic anhydride (2 mL), and the mixture was stirred at roomtemperature overnight. Upon completion, MeOH was added and thenconcentrated. The mixture was then dissolved in CH₂Cl₂ and washed withsaturated solution of sodium bicarbonate and brine, dried over MgSO₄ andconcentrated under reduced pressure to afford2-methoxy-6-(tosyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetateE6 (0.77 g, 94%).

Step 7: Preparation of2-(azidomethyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (E7)

To a solution of2-methoxy-6-(tosyloxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate(E6, 1.3 g, 2.7 mmol) in dry DMF (5 mL) was added sodium azide (0.88 g,13.5 mmol) and the mixture was heated at 80° C. overnight. The solventwas evaporated, and the residue was added CH₂Cl₂, filtered, concentratedunder reduced pressure and purified via column chromatography(EtOAc:hexane=1:10) to afford2-(azidomethyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate E7(0.75 g, 80%)

Step 8: Preparation of2-((4-(13-cyano-12-oxo-2,5,8-trioxa-11-azatridecyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate (E8)

2-(Azidomethyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate (E7,42 mg, 0.12 mmol) and2-cyano-N-(2-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)ethyl)acetamide (E4, 30mg, 0.12 mmol) were dissolved in H₂O/DMSO (1:2, 3 mL). Sodium ascorbate(20 mg, 0.1 mmol) and CuSO₄ (5 mg, 0.03 mmol) were added, and thesolution was stirred for 4 h. After the reaction, the solvents wereremoved under reduced pressure and the residue was extracted with EtOAc.The organic phase was dried, filtered and purified by columnchromatography (EtOAc:MeOH=20:1) to afford2-((4-(13-cyano-12-oxo-2,5,8-trioxa-11-azatridecyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetateE8 (50 mg, 70%).

Step 9: Preparation of(E)-2-((4-(13-cyano-12-oxo-14-(6-(piperidin-1-yl)naphthalen-2-yl)-2,5,8-trioxa-11-azatetradec-13-enyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate(E12)

The title compound was synthesized as described in Example 1, Step 6,using2-((4-(13-cyano-12-oxo-2,5,8-trioxa-11-azatridecyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate (E8) and 6-(Piperidin-1-yl)-2-naphthaldehyde (A6) as startingmaterials.

Step 10:(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide(Compound 19)

(E)-2-((4-(13-cyano-12-oxo-14-(6-(piperidin-1-yl)naphthalen-2-yl)-2,5,8-trioxa-11-azatetradec-13-enyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate (E12, 33 mg, 0.04 mmol) was dissolved in MeOH (2 mL) and asolution of K₂CO₃ (0.2 M, 0.5 mL) was then added at 0° C. The mixturewas stirred at room temperature for 0.5 h. After the reaction, theresidue was concentrated under reduced pressure and then purified bypreparative reverse-phase high-performance liquid chromatography(RP-HPLC) (grad. 5-90% acetonitrile in water, 30 min.) to afford(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-(2-(2-(2-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)ethoxy)ethoxy)ethyl)acrylamide(12 mg, 43%). ¹H NMR (CD₃OD, 500 MHz) δ 8.45 (s, 1H), 8.33 (s, 1H), 8.21(dd, J=9.0, 4.0 Hz, 1H), 8.18 (d, J=9.0 Hz, 1H), 8.12 (s, 1H), 8.07 (d,J=9.0 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J=9.0 Hz, 1H), 4.79 (dd, J=14.0,2.5 Hz, 1H), 4.63 (s, 2H), 4.60 (d, J=3.5 Hz, 1H), 4.49 (dd, J=14.0, 8.0Hz, 1H), 3.84-3.80 (m, 1H), 3.73 (t, J=6.0 Hz, 4H), 3.66 (s, 10H),3.61-3.56 (m, 3H), 3.35 (t, J=6.0 Hz, 1H), 3.11 (s, 3H), 2.06 (brs, 4H),1.84 (brs, 2H); ¹³C NMR (CD₃OD, 500 MHz) δ 161.9, 150.6, 144.3, 143.1,135.0, 132.3, 131.7, 130.7, 128.9, 128.8, 126.4, 125.2, 119.4, 118.3,115.8, 106.0, 99.8, 73.5, 71.9, 71.5, 70.3, 70.2, 70.1, 69.9, 69.3,68.8, 63.5, 55.7, 54.1, 51.0, 39.9, 23.8, 21.3; MS (ESI): m/z calc. forC₃₅H₄₆N₆O₉Na⁺: [M+Na]⁺ calcd for 717.33, found 717.44.

Example 8:(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide.See FIG. 16 for a Synthetic Scheme

Step 1: Preparation of 2-cyano-N-(prop-2-ynyl)acetamide (F5)

A mixture of methyl cyanoacetate (218 mg, 2.2 mmol) and propargylamine(122 mg, 2.2 mmol) was stirred at room temperature overnight. After thereaction, the residue was purified by column chromatography(EtOAc:hexane=1:1) to afford 2-cyano-N-(prop-2-ynyl)acetamide F5 (220mg, 82%).

Step 2: Preparation of2-((4-((2-cyanoacetamido)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate(F6)

2-(Azidomethyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate (E7,42 mg, 0.12 mmol) and 2-cyano-N-(prop-2-ynyl)acetamide (F5, 15 mg, 0.12mmol) were dissolved in H₂O/DMSO (1:1, 2 mL). Sodium ascorbate (20 mg,0.1 mmol) and CuSO₄ (5 mg, 0.03 mmol) were added, and the solution wasstirred for 2 h. After the reaction, the solvents were removed underreduced pressure and the residue was extracted with EtOAc. The organicphase was dried, filtered and purified by column chromatography(EtOAc:MeOH=30:1) to afford2-((4-((2-cyanoacetamido)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetateF6 (45 mg, 80%)

Step 3: Preparation of(E)-2-((4-((2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamido)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate(F10)

To a round bottom flask containing a solution of6-(Piperidin-1-yl)-2-naphthaldehyde (A6, 10 mg, 0.042 mmol) and2-((4-((2-cyanoacetamido)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate(F6, 20 mg, 0.042 mmol) in THF (2.0 mL), piperidine (50 μL) was addedand the mixture refluxed 1 h. The crude mixture was concentrated underreduced pressure and the product was purified via flash columnchromatography (EtOAc: CH₂Cl₂=10:1) to afford(E)-2-((4-((2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamido)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate F10 (18 mg, 62%).

Step 4: Preparation of(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide(Compound 20)

(E)-2-((4-((2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylamido)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyltriacetate(F10, 10 mg, 0.015 mmol) was dissolved in MeOH (2 mL) and a solution ofK₂CO₃ (0.3 M, 0.2 mL) was then added at 0° C. The mixture was stirred atroom temperature for 0.5 h. After the reaction, the residue wasconcentrated under reduced pressure and then purified by preparativereverse-phase high-performance liquid chromatography (RP-HPLC) (grad.5-90% acetonitrile in water, 30 min.) to afford(E)-2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)-N-((1-((3,4,5-trihydroxy-6-methoxytetrahydro-2H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acrylamide(4.5 mg, 54%). ¹H NMR (CD₃OD, 500 MHz) δ 8.40 (s, 1H), 8.33 (s, 1H),8.19 (dd, J=8.5, 2.0 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.98 (d, J=9.0 Hz,2H), 7.83 (s, 1H), 7.66 (dd, J=9.0, 2.0 Hz, 1H), 4.85 (d, J=2.0 Hz, 1H),4.82 (d, J=2.0 Hz, 1H), 4.62 (s, 3H), 4.50 (dd, J=14, 8.5 Hz, 1H),3.84-3.80 (m, 1H), 3.64 (t, J=5.5 Hz, 4H), 3.60 (t, J=9.0 Hz, 1H), 3.36(dd, J=9.5, 4.0 Hz, 1H), 3.14 (s, 3H), 1.96 (brs, 4H), 1.79 (brs, 2H);¹³C NMR (CD₃OD, 500 MHz) δ 163.7, 152.9, 145.9, 137.6, 134.3, 134.3,132.2, 130.7, 129.7, 129.3, 127.1, 125.8, 120.8, 117.5, 114.9, 104.9,101.3, 74.9, 73.3, 72.9, 71.8, 71.7, 55.7, 55.6, 53.9, 52.5, 36.5, 25.9,24.1; MS (ESI): m/z calc. for C₂₉H₃₅N₆O₆ ⁺: [M+H]⁺ calcd for 563.26,found 563.35.

Example 9: In vitro amyloid binding and tissue staining studies

Extensive in vitro work demonstrate that Compound 1 (FIG. 13A) displaysprivileged properties in terms of an ability to bind selectively toamyloids and emit a characteristic fluorescence upon binding toAlzheimer's related amyloids. FIG. 2A and FIG. 2B show the absorbanceand emission profile of compound 1 free in solution (solid line) andbound (dashed line) to aggregated Alzheimer's-related peptide (A1342).FIG. 2C shows a plot of fluorescence intensity versus concentration ofcompound 1 in the presence of aggregated Aβ(1-42) peptide. AggregatedAβ(1-42) at a final concentration of 10 μM (based on the molecularweight of monomer) was mixed with increasing concentration of compound 1(0, 0.25, 0.5, 1, 2, 4, 8 μM) in 5% DMSO in PBS. The K_(a) wasdetermined by fitting data to a one-site specific binding algorithm:Y=B_(mx)·X/(K_(d)+X), where X is the concentration of the probe, Y isthe specific binding fluorescence intensity, and B_(max) corresponds tothe apparent maximal observable fluorescence upon binding of probes toaggregated Aβ(1-42) peptide.

In order to test whether Compound 1 could discriminate amyloids based ondisease origin, the spectroscopic properties of Compound 1 when bound toamyloids derived from amyloid-β (associated with Alzheimer's disease),PrP (associated with CJD), and α-synuclein (associated with Parkinson'sdisease) were examined. FIG. 18 shows that Compound 1 can distinguishbetween amyloids of different disease origin based on color of emission.These results demonstrate the potential specificity that Compound 1 canhave for conclusively identifying amyloid deposits from AD patientsversus any other disease origin.

Example 10: Stability and Solubility Studies for Compound 1

The rate of hydrolytic decomposition of Compound 1 in PBS (with 5% DMSOto aid in solubility) at 25° C. by HPLC was examined. FIG. 19A shows therelative abundance of Compound 1 over a 24 hour period. These studiesreveal that Compound 1 has a t_(1/2) for hydrolysis of ˜150 hours. Forcomparison, ANCA-11 ((E)-2-(2-(2-methoxyethoxy)ethoxy)ethyl2-cyano-3-(6-(piperidin-1-yl)naphthalen-2-yl)acrylate) exhibited at_(1/2) for hydrolysis of ˜11 hours under the same conditions. Incertain in vivo environments (especially at high or low pH or in thepresence of esterases), ANCA-11 is expected to decompose very rapidlydue to the poor stability of its ester functionality. The amidefunctionality in Compound 1 alleviates the problem of hydrolyticinstability inherent to ANCA-11.

Some initial solubility studies have been carried out on Compound 1(table 1). Compound 1 was soluble at a concentration of >5 mg/mL in alloils tested (Castor Oil (Ricinus Oil), Castor Oil (Ethyoxylated), cornoil, cotton seed oil, sesame oil, soyabean oil, and peanut oil).

TABLE 1 Solubility studies on Compound 1 Solvent System Solubility(mg/mL) Soybean Oil 2.0 Sesame Oil 2.0 Castor Oil <0.01 Peanut Oil 1.7Corn Oil 1.3 Cotton Seed Oil 2.0 PEG400 20.0 Cremophor EL <0.01Isopropyl Myristate 6.0 Isopropyl Palmitate 5.0 Medium Chain 6.0Triglycerides Tetraglycol 11.0 Tricapylin 20.0 5% beta-cyclodextrin 0.810% beta-cyclodextrin 1.8 20% beta-cyclodextrin 3.33

Additionally the solubility was tested in water miscible solvents suchas Benzyl alcohol, PEG 400, Ethylene Glycol, Polysorbate 20, DiethyleneGlycol Monoethyl ether, 10% aqueous Poloxamer-188, Glycerol, 10% aqueousPoloxamer-407, Poloxamer 124. Compound 1 was very soluble in alcoholssuch as benzyl alcohol, propylene glycol, polysorbates and PEGs to aconcentration of >5 mg/mL. For the others listed, the solubility was 2-3mg/ml.

Additionally the solubility was tested in Surfactants such as: Tween 20,Tween 80, ethyl oleate, isopropyl myristate, Neobee M-5. In thesesolvents, Compound 1 was very well soluble to a concentration of >5mg/mL.

The solubility of Compound 1 in water increased as the pH was lowered toa pH<5 (See FIG. 19B).

These data are crucial to help with developing a suitable formulationfor IV or topical administration of the probe for retinal imaging ofamyloid in AD patients.

Compound 1 Solubility in Various Acids:

Solubility of Compound 1 was tested in HCl, acetic, citric, succinic,and lactic acid buffer (20-50 mM) and at pH 2-6. At lower pH and higherbuffer concentration, the solubility increased up to 350 μg/mL vs waterwhich is 3 μg/mL, representing a 100 fold increase. A representativeexample is shown in FIG. 19C for citric acid buffer.

Table 2 shows that at lower pH and higher acidic buffer strength, thesolubility of Compound 1 can be increased to more than 6 mg/mL. The HClsalt of Compound 1 is more soluble than the base in water and phosphatebuffer. Phosphate buffer tends to decrease the solubility of the HClsalt.

TABLE 2 Sample Conc (mg/mL) Compound 1 in H₂O 0.0031 Compound 1 in 10 mMphosphate buffer, 0.0074 pH 7.4 Compound 1HCl salt in water 1.9612Compound 1 HCl salt in 10 mM phos buffer, 0.1686 pH 7.4 Compound 1 in 10mM HCl (pH 2.5) 1.6299 Compound 1 in 10% aq. acetic acid (pH 3.4) 2.8526Compound 1 in 10% aq. citric acid (pH 3.4) 6.5916

Example 11: Salt of Compound 1 Preparation and Stability Preparation ofthe HCl Salt:

Compound 1 dissolved and stirred in 3 molar equivalents of methanolicHCl at 0° C. for 4 hrs at 27° C. Methanol was removed and the solid wastriturated with dry ethyl ether (5×10 mL) and dried in high vacuumovernight. Structure and purity was determined by analytical HPLC(comparing retention time to base), proton NMR, and mass spectrometricanalysis. Mass Analysis of Compound 1 vs Compound 1-HCl salt: (ES, m/z):[M+H]⁺452 (FIG. 24A). ¹H-NMR-(500 MHz, CDCl₃) analysis of Compound 1 HClsalt: Proton NMR confirmed the protonation of piperazine by analyzingthe shifts in the NMR spectrum.

Compound 1. ¹H NMR (500 MHz, CDCl₃) δ 8.33 (s, 1H), 8.11 (s, 1H),8.00-8.02 (dd, J=8.5 Hz, 1.5 Hz, 1H), 7.69-7.71 (d, J=9.5 Hz, 1H),7.60-7.62 (d, J=8.5 Hz, 1H), 7.24-7.26 (m, 1H), 7.01 (bs, 1H), 6.84 (m,1H), 3.64-3.66 (m, 6H), 3.62-3.63 (m, 4H), 3.54-3.55 (m, 2H), 3.35 (s,3H), 3.12-3.34 (m, 4H), 1.69 (m, 4H), 1.61-1.62 (m, 2H)

Compound 1-HCl: ¹H-NMR (500 MHz, CDCl₃): δ 8.59 (s, 1H), 8.44 (s, 1H),8.37 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 8.02 (d,J=9 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 6.94-6.95 (m, 1H), 3.64-3.68 (m,11H), 3.55-3.57 (m, 5H), 3.36 (s, 3H), 2.37 (bd. s, 4H), 1.83 (bd, m,2H)

Preparation of the Citrate Salt:

Compound 1 was dissolved in ethanol to which 1.2 molar equivalents ofcitric acid was added. The mixture was sonicated for dissolution,stirred at room temperature for 2 hrs and cooled to −4° C. Theprecipitate was filtered, washed with cold ethyl ether and dried underhigh vacuum. The sample was analyzed by analytical HPLC and retentiontime was confirmed to be that of parent, establishing the identity ofthe salt.

Solubility of the Citrate Salt

Solubility of citrate salt is 0.25 mg/ml, an increase of 140 fold versuswater at pH 3.5. By comparison, the HCl salt of Compound 1 has a watersolubility of 1.96 mg/ml.

Example 12: Ex Vivo Studies

Transgenic mice (J20) that overexpress the Swedish and Indiana mutantforms of amyloid precursor protein (APP) and produce human beta-amyloidserved as a convenient murine model of Alzheimer's disease pathogenesis.Six J20 mice (and six wt littermate controls), bred and aged to 21months, were dosed systemically (through the tail vein) with compound 1(Test formulation: 100-150 μL of a 500 μM solution of compound 1 in 80%Propylene glycol/20% DMSO for in vivo injection) or vehicle alone. Afterinjection, all mice were allowed to run free in the cage for 30 minutes.Mice were then sacrificed and the retinal tissue was harvested andvisualized for compound 1 staining.

For ex vivo analysis of retina, the eyes of J20 or wt mice injected withcompound 1 or vehicle alone were removed from the mice within 1 minuteof sacrifice and put on ice. The eyes were then dissected to remove theretina within 1 hour of sacrifice. Retina were then subjected to a short5 minute methanol dehydration/fixation step, and then incubated withDAPI (nuclear stain), red fluorescent lectin (vascular stain), and ananti-Aβ antibody (followed by a fluorescently labelled secondaryantibody). The retina were then flat mounted onto a glass coverslip andimaged via confocal microscopy.

FIG. 20A and FIG. 20B show a 3D z-stack reconstruction of the retina ofa J20 mouse injected with compound 1 30 minutes prior to sacrifice. Thewhite arrows in FIG. 20A highlights several bright objects within theneuronal layers of the retina that are stained with compound 1. Amyloiddeposits in the retina of tg mice and humans with AD have been reportedto develop within the neuronal layers as a function of diseaseprogression (Neuroimage 2011, 54, S204-S217). FIG. 20B is an image ofthe same retina shown in FIG. 20A, but highlighting only the location(white arrows) of the amyloid deposits stained by the anti-Aβ antibody(followed by a fluorescently labelled secondary antibody). The anti-Aβantibody (highlighted by the white arrows in FIG. 20B) and compound 1(highlighted by the white arrows in FIG. 20A) co-localize in the retina,providing very strong evidence that compound 1 can cross theblood-retina barrier and specifically stain amyloids in the retina afterin vivo systemic administration.

Example 13: Imaging of Amyloid Deposits in Live Animals

In addition to the visualization of amyloid deposits through theharvesting of tissues and ex vivo imaging, recent efforts have shown theability to image amyloid deposits in live animals. Three transgenic ADmice (hAPP/PS1, J20, and 5XFAD) mice have been bred and aged forimaging. While these AD tg mouse models age, an animal model of CJD,that has a much shorter timeline for amyloid deposit accumulation, hasbeen investigated for live imaging of retinal amyloid accumulation afterIP administration of Compound 1. Mice were anesthetized with ketamineand placed on a stage affixed with a 37° C. heating pad. The retina wereimaged via bright field and fluorescence using a Phoenix LaboratoryMicron TV rodent retinal microscope to establish

a baseline image.

Mice inoculated with GPI-anchorless strain of PrP served as an initialconvenient animal model for Creutzfeldt-Jakobs Disease, and has beeninvestigated for live imaging of retinal amyloid accumulation after IPadministration of compound 1. For this demonstration, compound 1, dosedvia intraperitoneal injection (Formulation: 200 μL of a 10 mg/mLsolution of compound 1 in 20% DMSO/80% propylene glycol), allowed forthe visualization of amyloid deposits in the retina.

FIG. 21A shows a bright field image of the retina of an anesthetized wtmouse. FIG. 21B shows a bright field image of the retina of ananesthetized prion-infected (156 days post infection with GPI-anchorlessPrP) mouse (J. Virol., 2011, 85, 1484-1494). The bright field images ofthe two different mice shown in FIG. 21A and FIG. 21B are notsufficiently different as to distinguish a healthy versus diseased mouse(the dark area within each image is an artifact of the objectives on therodent microscope [Phoenix labs Micron IV rodent retinal microscope]used to obtain these live mouse retinal images). FIG. 21C shows afluorescence image of the retina of the wt mouse (same mouse retinashown in FIG. 21A) immediately after IP injection with compound 1. Thedull background fluorescence observable in FIG. 21C, as well as theslightly brighter green fluorescence seen in the retinal vasculature,demonstrates that compound 1 immediately accumulates in the blood and inthe retinal tissue after IP injection. This dull background fluorescenceis expected to fade over time as compound 1 is cleared from the mouse.FIG. 21D shows a fluorescence image of the retina of the prion-infectedmouse (same mouse retina shown in FIG. 21B) immediately after IPinjection with compound 1. FIG. 21D reveals very bright objects (due tostaining with compound 1) located throughout the retina (highlightedwith white arrows). These objects are consistent with prion amyloiddeposits that have previously been reported to accumulate in the retinaof mice inoculated with GPI-anchorless PrP (J. Virol., 2011, 85,1484-1494).

FIG. 22A and FIG. 22B show a comparison of the fluorescence image of theretina of a living prion-infected mouse injected with Compound 1 and theretina of same mouse after sacrifice, removal of the retina, andexamination ex vivo by confocal microscopy. FIG. 22A is the same as FIG.21D. FIG. 22B reveals many bright fluorescent objects (highlighted withwhite arrows) stained in vivo with Compound 1. No further processing(i.e., no further staining with Compound 1) was performed on the retinaltissue to obtain the fluorescence image in FIG. 22B. Taken together, theresults shown in FIGS. 21A-D and FIGS. 22A-B provide strong evidencethat Compound 1 can quickly and readily be used for in vivo retinaimaging of amyloid deposits as an indicator of disease.

FIG. 23 shows a magnified, true color micrograph of an individual prionplaque from the same eye shown in FIG. 22. Spectroscopic inspection ofCompound 1 bound to this amyloid deposit revealed a λ_(max) (Em)=554 nm,which precisely matched the emission wavelength of Compound 1 bound toprion plaques found in the brain. This result demonstrates that thespectroscopic specificity of Compound 1 for identifying anddiscriminating amyloid deposits from different disease origins can beachieved in the retina in an analogous manner as has been demonstratedin other parts of the brain.

1. (canceled)
 2. A method for monitoring the response of a patienthaving a disease or condition characterized by amyloid deposit to atreatment, comprising: (i) forming a detectable complex following thetreatment by contacting an effective amount of a compound of Formula Ic,or a salt or solvate thereof, or a pharmaceutical composition thereof,with a sample, a body part, or a body area of the patient; and (ii)detecting the formation of the detectable complex, wherein a decrease ofdetectable complex as compared to before the treatment indicates thatthe patient is responsive to the treatment; wherein the compound ofFormula Ic has the structure:

wherein EDG is heterocycloalkyl of no more than 10 carbons optionallysubstituted with one or more R₁₇; each R₁₇ is independently halogen,—OR₁₈, —NR₁₉R₂₀, C₁-C₁₀ alkyl, or C₁-C₁₀ heteroalkyl; each of R₁₈, R₁₉and R₂₀ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl, orcycloalkyl of no more than 10 carbon atoms, each of which except forhydrogen is optionally substituted with one or more R₂₁; each R₂₁ isindependently halogen, —OR₂₂, —NR₂₃R₂₄, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, cycloalkyl of no more than 10 carbon atoms,heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than10 carbon atoms, or heteroaryl of no more than 10 carbon atoms; each ofR₂₂, R₂₃ and R₂₄ is independently hydrogen or C₁-C₁₀ alkyl; Ar isarylene of no more than 14 carbon atoms optionally substituted with oneor more R₁; each R₁ is independently halogen, —OR₂, —NR₃R₄, C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl; each of R₂, R₃ and R₄ is independentlyhydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ heteroalkyl; R₈₄ is hydrogen or C₁-C₁₀alkyl; EWG is halogen, —CN, —NO₂, or methyl; WSG is:

wherein n is an integer from 2-50, and R₈₁ is hydrogen, a C₁-C₁₀ alkyl,a C₂-C₁₀ alkenyl, or a C₂-C₁₀ alkynyl, wherein the alkyl, alkenyl, oralkynyl is optionally substituted with one or more C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, cycloalkyl of no more than 10 carbon atoms,heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than10 carbon atoms, or heteroaryl of no more than 10 carbon atoms; each R₈₂is independently hydrogen or C₁-C₁₀ alkyl; X is C═O or SO₂; and Y is NHor S.
 3. The method of claim 2, in which the amyloid deposit comprisesan amyloid or amyloid like protein, wherein the amyloid or amyloid likeprotein is Aβ peptide, prion peptide, alpha-synuclein, or superoxidedismutase.
 4. The method of claim 3, wherein the amyloid or amyloid likeprotein is beta amyloid (1-42) (Aβ (1-42)).
 5. The method of claim 2,wherein EDG is selected from


6. The method of claim 2, wherein EDG is


7. The method of claim 2, wherein EWG is —CN.
 8. The method of claim 2,wherein R₈₄ is hydrogen or methyl.
 9. The method of claim 2, wherein WSGis:

wherein R₈₁ is methyl or CH₂—C≡CH, wherein n is 2, 3, 4, 5, 6, 7, 8, 9,or 10;


10. The method of claim 2, wherein WSG is

wherein n is an integer from 2-50 and R₈₁ is C₁-C₁₀ alkyl.
 11. Themethod of claim 2, wherein R₈₁ is methyl.
 12. The method of claim 2,wherein n is 3 or
 6. 13. The method of claim 2, wherein the compound is:

wherein n is an integer from 2 to 10, and n′ is an integer from 2 to 10.14. The method of claim 2, wherein the compound is:


15. The method of claim 2, wherein the compound is:


16. The method of claim 2, wherein the disease or condition isAlzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, Lewy body dementia, or Down's syndrome.17. The method of claim 2, wherein the disease or condition is a priondisease or condition.
 18. The method of claim 2, wherein the disease orcondition is Creutzfeldt-Jakob disease.
 19. A method for monitoring theresponse of a patient having a disease or condition characterized byamyloid deposit to a treatment, comprising (i) forming a detectablecomplex following the treatment by contacting an effective amount of acompound of the formula:

or a salt or solvate thereof, or a pharmaceutical composition thereof,with a sample, a body part, or a body area of the patient; and (ii)detecting the formation of the detectable complex, wherein a decrease ofdetectable complex as compared to before the treatment indicates thatthe patient is responsive to the treatment.
 20. A method of detecting anamyloid or amyloid like protein comprising (i) contacting a compound ofFormula Ic, or a salt or solvate thereof, with a sample potentiallycomprising the amyloid or amyloid like protein, wherein in presence ofan amyloid or amyloid like protein the compound forms a detectablecomplex; and (ii) detecting the formation of the detectable complex suchthat the presence or absence of the detectable complex correlates withthe presence or absence of the amyloid or amyloid like protein; whereinthe compound of Formula Ic has the structure:

wherein EDG is heterocycloalkyl of no more than 10 carbons optionallysubstituted with one or more R₁₇; wherein each R₁₇ is independentlyhalogen, —OR₁₈, —NR₁₉R₂₀, C₁-C₁₀ alkyl, or C₁-C₁₀ heteroalkyl; each ofR₁₈, R₁₉ and R₂₀ is independently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, or cycloalkyl of no more than 10 carbon atoms, each ofwhich except for hydrogen is optionally substituted with one or moreR₂₁; each R₂₁ is independently halogen, —OR₂₂, —NR₂₃R₂₄, C₁-C₁₀ alkyl,C₁-C₁₀ heteroalkyl, cycloalkyl of no more than 10 carbon atoms,heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than10 carbon atoms, or heteroaryl of no more than 10 carbon atoms; each ofR₂₂, R₂₃ and R₂₄ is independently hydrogen or C₁-C₁₀ alkyl; Ar is arylof no more than 14 carbon atoms optionally substituted with one or moreR₁; each R₁ is independently halogen, —OR₂, —NR₃R₄, C₁-C₁₀ alkyl, C₁-C₁₀heteroalkyl, each of R₂, R₃ and R₄ is independently hydrogen, C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl; R₈₄ is hydrogen or C₁-C₁₀ alkyl; EWG ishalogen, —CN, —NO₂, or methyl; WSG is:

wherein n is an integer from 2 to 50, and R₈₁ is hydrogen, a C₁-C₁₀alkyl, a C₂-C₁₀ alkenyl, or a C₂-C₁₀ alkynyl, wherein the alkyl,alkenyl, or alkynyl is optionally substituted with one or more C₁-C₁₀alkyl, C₁-C₁₀ heteroalkyl, cycloalkyl of no more than 10 carbon atoms,heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than10 carbon atoms, or heteroaryl of no more than 10 carbon atoms; each R₈₂is independently hydrogen or C₁-C₁₀ alkyl; X is C═O or SO₂; and Y is NHor S.
 21. The method of claim 20, wherein the sample is from a patienthaving a disease or condition selected from the group consisting ofAlzheimer's disease, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis, Lewy body dementia, Down's syndrome, andCreutzfeldt-Jakob disease.